entryList

entry status live allelicVariantExists true epochCreated 790416000 geneMap geneSymbols COMP, EDM1, MED, PSACH sequenceID 12867 phenotypeMapList phenotypeMap phenotypeMimNumber 132400 mimNumber 600310 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 132400 phenotypeMappingKey 3 phenotype Epiphyseal dysplasia, multiple 1 phenotypeMappingKey 3 mimNumber 600310 phenotypeInheritance Autosomal dominant phenotype Pseudoachondroplasia phenotypeMimNumber 177170 chromosomeLocationStart 18893582 chromosomeSort 376 chromosomeSymbol 19 mimNumber 600310 geneInheritance None confidence P mappingMethod REa, A, Fd geneName Cartilage oligomeric matrix protein mouseMgiID MGI:88469 mouseGeneSymbol Comp computedCytoLocation 19p13.11 cytoLocation 19p13.1 transcript uc002nke.3 chromosomeLocationEnd 18902113 chromosome 19 contributors Patricia A. Hartz - updated : 10/17/2013 Marla J. F. O'Neill - updated : 7/11/2012 George E. Tiller - updated : 11/12/2010 Victor A. McKusick - updated : 1/11/2005 Natalie E. Krasikov - updated : 3/30/2004 Victor A. McKusick - updated : 8/19/2003 Victor A. McKusick - updated : 12/30/2002 Victor A. McKusick - updated : 12/13/2002 Sonja A. Rasmussen - updated : 7/10/2002 Joanna S. Amberger - updated : 6/7/2002 Sonja A. Rasmussen - updated : 12/7/2001 Victor A. McKusick - updated : 9/20/2001 Victor A. McKusick - updated : 4/12/2001 Sonja A. Rasmussen - updated : 10/1/1999 Victor A. McKusick - updated : 2/18/1999 Victor A. McKusick - updated : 2/1/1999 Victor A. McKusick - updated : 1/20/1999 Victor A. McKusick - updated : 1/15/1999 Victor A. McKusick - updated : 4/18/1998 Victor A. McKusick - updated : 6/18/1997 Victor A. McKusick - updated : 3/27/1997 clinicalSynopsisExists false mimNumber 600310 allelicVariantList allelicVariant status live name PSEUDOACHONDROPLASIA dbSnps rs137852650 text In a family with pseudoachondroplasia ({177170}), {12:Hecht et al. (1995)} demonstrated a G-to-T transversion at nucleotide 1439 of the COMP gene, resulting in an asp472-to-tyr amino acid substitution. The single nucleotide substitution occurred in 1 of the 5 GAC repeats, converting GAC to TAC. mutations COMP, ASP472TYR number 1 clinvarAccessions RCV000009761;;1 status live name PSEUDOACHONDROPLASIA dbSnps rs137852651 text In an isolated case of pseudoachondroplasia ({177170}), {12:Hecht et al. (1995)} observed a G-to-A transition at nucleotide 1428 of the COMP gene, leading to a cys468-to-tyr amino acid substitution. mutations COMP, CYS468TYR number 2 clinvarAccessions RCV000009762;;1 status live name PSEUDOACHONDROPLASIA text In an isolated case of pseudoachondroplasia ({177170}), {12:Hecht et al. (1995)} observed deletion of nucleotides 1400-1402 (TCA) of the COMP gene, resulting in deletion of serine-459. mutations COMP, 3-BP DEL, 459TCA, SER459DEL number 3 clinvarAccessions RCV000009763;;1 status live name PSEUDOACHONDROPLASIA text In 5 unrelated patients with pseudoachondroplasia ({177170}), including 1 from a family originally reported by {11:Hall and Dorst (1969)}, {12:Hecht et al. (1995)} identified a 3-bp deletion removing 1 of the 5 GAC repeat sequences at cDNA nucleotides 1430-1445 of the COMP gene. This resulted in the loss of an aspartate residue in a calcium-binding site. In 2 sporadic patients and affected members of 5 families with PSACH, {5:Briggs et al. (1998)} identified heterozygosity for a 3-bp deletion (delGAC 1430-1444) in exon 13 of the COMP gene, resulting in removal of 1 of 5 consecutive aspartic acid residues corresponding to codons 469 to 473 within the seventh calmodulin-like repeat. The authors noted that the repeated nature of the GAC sequence did not allow precise determination of the codon that was deleted in the patients. In 3 sporadic patients with PSACH, {16:Ikegawa et al. (1998)} identified heterozygosity for a 3-bp deletion within the (GAC)5 trinucleotide repeat region in exon 13. {16:Ikegawa et al. (1998)} noted that, like the previously reported patients with this mutation, the phenotype was severe in all 3 patients, their adult heights being less than 110 cm. {3:Briggs and Chapman (2002)} reviewed mutations in the COMP gene resulting in PSACH and, using nucleotide numbering from the start site of translation, designated this nucleotide change as 1405-1419 delGAC and the corresponding protein change as delD(469-473). This mutation is thought to account for approximately one-third of PSACH patients. It is a contraction of a short trinucleotide repeat; expansion of this repeat to (GAC)6 and (GAC)7 are represented by 2 other entries, {600310.0012} and {600310.0011}, respectively ({8:Delot et al., 1999}). Deletion of 1 of the 5 asp codons in the type 3 calcium-binding domain of COMP essentially deletes the single asp470 spacer between calcium-binding loops 10 and 11. {18:Kleerekoper et al. (2002)} created recombinant mutant COMP proteins that carried a deletion of asp470, mimicking the deletion found in PSACH patients, and found that this deletion decreased the calcium binding capacity of COMP. Calcium binding by this domain is required to nucleate folding. The authors predicted that persistence of the unstructured state of the mutated calcium-binding domain would lead to retention of COMP in the rough endoplasmic reticulum of differentiated PSACH and EDM1 chondrocytes. mutations COMP, 3-BP DEL, (GAC)4 number 4 clinvarAccessions RCV000009764;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1, SEVERE dbSnps rs137852652 text In a patient with a severe form of multiple epiphyseal dysplasia 1 ({132400}), {4:Briggs et al. (1995)} identified a de novo heterozygous mutation in the COMP gene, resulting in an asp342-to-tyr (D342Y) substitution in a conserved residue in the third calmodulin-like repeat. The mutation created an RsaI restriction endonuclease cleavage site. mutations COMP, ASP342TYR number 5 clinvarAccessions RCV000009765;;1 status live name PSEUDOACHONDROPLASIA dbSnps rs137852653 text In an affected individual from a family with a moderately severe form of pseudoachondroplasia ({177170}), {4:Briggs et al. (1995)} found heterozygosity for a point mutation that predicted substitution of arginine for the cysteine at residue 328 (cys328-to-arg; C328R). The mutation altered a conserved residue in the second calmodulin-like repeat of COMP. The change created a new cleavage site which was identified in genomic DNA in all 4 affected members of the family but in no unaffected individuals. mutations COMP, CYS328ARG number 6 clinvarAccessions RCV000009766;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1, MILD dbSnps rs137852654 text In affected members of a South African family with a mild form of EDM1 ({132400}), {2:Ballo et al. (1997)} identified a heterozygous 1594C-G transversion in the COMP gene, resulting in an asn523-to-lys (N523K) substitution, which altered a residue at the C-terminal end of the calmodulin-like region of the protein. There were affected individuals in 3 generations. Radiologic findings in a mother and son included flattening and irregularity of femoral heads and unevenness of the intraarticular aspects of the distal end of the femurs and proximal end of the tibias. The lateral femoral condyles were hypoplastic. The endplates of the vertebral bodies showed mild sclerosis and irregularity, but there was no significant flattening. {2:Ballo et al. (1997)} stated that the identification of this mutation demonstrates that the spectrum of manifestations from mild MED through pseudoachondroplasia can all be produced by structural mutations in COMP. mutations COMP, ASN523LYS number 8 clinvarAccessions RCV000009767;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1, SEVERE dbSnps rs28936668 text In a patient with a severe form of EDM1 ({132400}), {5:Briggs et al. (1998)} found a 1383A-G transition in exon 13 of the COMP gene which resulted in an asn453-to-ser (N453S) amino acid substitution located in the calmodulin-like domain 7. The proband was first seen at the age of 15 years when she was short of stature (height 144 cm) and complained of pain in the knees. The hands were normal. Radiographs showed normal hands and hips, but the tibial epiphyses were irregular, with a squared aspect. Her affected sister was also short of stature and had involvement of the knees and hips. The femoral head was small and irregular, but the severity of the deformities was somewhat less striking those of other cases of MED Fairbank. The affected father had knee involvement but the hips were unaffected. The affected grandmother had severe hip dysplasia that required surgical replacement of the femoral head. mutations COMP, ASN453SER number 9 clinvarAccessions RCV000009768;;1 status live name PSEUDOACHONDROAPLASIA dbSnps rs28936669 text In a sporadic case of pseudoachondroplasia ({177170}), {15:Ikegawa et al. (1998)} described an interstitial deletion in 11q. In a subsequent sequence analysis, ({14:Ikegawa, 1998}) identified a 1418A-G transition in the COMP gene, resulting in an asp473-to-gly (D473G) amino acid substitution. The deletion was apparently fortuitous; since the mutation was de novo (absent in the normal parents) and substituted a highly conserved aspartic acid residue, it was presumably the cause of the disorder. mutations COMP, ASP473GLY number 10 clinvarAccessions RCV000009769;;1 status live name PSEUDOACHONDROPLASIA text In a sporadic case of pseudoachondroplasia {177170}, {8:Delot et al. (1999)} identified an expansion of the short trinucleotide repeat, (GAC)5, located at cDNA dinucleotides 1430 to 1444 of the COMP gene. The patient was found to be heterozygous for a (GAC)7 allele. The diagnosis of typical PSACH had been established at 3 years of age. mutations COMP, 6-BP INS, (GAC)7 number 11 clinvarAccessions RCV000009770;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1 dbSnps rs312262898 text In a patient with multiple epiphyseal dysplasia-1 ({132400}) from a family with autosomal dominant inheritance, {8:Delot et al. (1999)} found an expansion of the short (GAC)5 repeat; the patient was heterozygous for a (GAC)6 allele. The diagnosis of EDM1 had been established at the age of 13 years; she was noted to have short stature and radiographic abnormalities confined to the epiphyses of the long bones. The affected mother had undergone surgery to replace the left and right hips at 35 and 37 years of age, respectively. The adult height of the proband was 153 cm and her affected mother was 160 cm tall. By comparison, 2 unaffected females in the family were 168 and 173 cm tall. A brother was more severely affected and underwent bilateral osteotomies at 16 years of age for genu varum. The proband underwent hip replacement surgery at age 34, at which time cartilage and tendon from the femoral head were obtained. mutations COMP, 3-BP INS, (GAC)6 number 12 clinvarAccessions RCV000009771;;2;;;RCV000033881;;1 status live name PSEUDOACHONDROPLASIA, SEVERE dbSnps rs137852655 text {20:Mabuchi et al. (2001)} reported a case with severe pseudoachondroplasia ({177170}), including marked short stature and deformities of the spine and extremities. The patient had a G-to-A transition (GGT-GAT) at nucleotide 2156 in exon 18 of the COMP gene. The mutation was predicted to cause a gly719-to-asp (G719D) substitution in the C-terminal globular domain and was the first case with a severe pseudoachondroplasia phenotype with a mutation outside the seventh calmodulin-like repeat. mutations COMP, GLY719ASP number 13 clinvarAccessions RCV000033890;;1;;;RCV000009772;;1 status live name PSEUDOACHONDROPLASIA dbSnps rs137852656 text {32:Unger et al. (2001)} reported a child with double heterozygosity for pseudoachondroplasia ({177170}), resulting from a cys348-to-arg mutation in the COMP gene, and spondyloepiphyseal dysplasia congenita ({183900}), resulting from a mutation in the COL2A1 gene ({120140.0035}). The child inherited pseudoachondroplasia from his mother and spondyloepiphyseal dysplasia congenita from his father. He had clinical and radiographic findings that were more severe than those in either disorder alone. mutations COMP, CYS348ARG number 14 clinvarAccessions RCV000009773;;1 status live name PSEUDOACHONDROPLASIA text {22:Mabuchi et al. (2003)} described a 533-bp deletion extending from exon 9 to intron 9 of the COMP gene in a patient with severe pseudoachondroplasia ({177170}); his height was below -8 SD and his joint involvement was multiple and severe. The aberrant allele would significantly affect the conformation of the COMP protein. mutations COMP, EX9DEL number 15 clinvarAccessions RCV000009774;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1, MILD text In a patient with a mild form of multiple epiphyseal dysplasia 1 ({132400}), {22:Mabuchi et al. (2003)} described a cytosine inserted between nucleotides 2223 and 2224 in the C-terminal part of the COMP gene. The insertion changed codon 742 from AAT (asn) to CAA (gln) with a frameshift that changed codon 743 from GAC (asp) to TGA (ter); the mutation was symbolized N742fsX743. Asn742, the first affected amino acid, is the predicted site for N-linked glycosylation. The insertion caused premature termination of the codon and a truncated COMP protein. The mutation was located immediately following cys741. Although the frameshift mutation was predicted to produce a considerably truncated protein (15 amino acids shorter), the phenotypic effect was mild. Members of the family showed involvement of the hip and knee joints, but their stature was normal. Therefore, the sequence following cys741 may have little impact for COMP function. mutations COMP, 1-BP INS, 2223C number 16 clinvarAccessions RCV000009775;;1 status live name EPIPHYSEAL DYSPLASIA, MULTIPLE, 1 dbSnps rs28936368 text In a patient with a severe form of multiple epiphyseal dysplasia 1 ({132400}), {22:Mabuchi et al. (2003)} identified a 2152C-T transition in exon 18 of the COMP gene, resulting in an arg718-to-trp (R718W) substitution. {17:Jakkula et al. (2003)} identified the same mutation in patients with EDM1 who had muscle weakness, moderate creatine kinase elevation, and MED beginning with the knee joints. No disease-causing mutations were detected in collagen IX genes. mutations COMP, ARG718TRP number 17 clinvarAccessions RCV000009776;;2 status live name PSEUDOACHONDROPLASIA text In an individual with moderately severe pseudoachondroplasia ({177170}), {4:Briggs et al. (1995)} identified heterozygosity for a 3-bp deletion in exon 10 of the COMP gene, which eliminated a codon for an aspartic acid residue from the (GAC)3 repeat within the fourth calmodulin-like repeat. Due to the repeated sequence of nucleotides 1139-1147, it was not possible to determine which 3 nucleotides were deleted and, hence, which aspartic acid codon (372-374) was eliminated. The occurrence of the deletion in a series of direct repeats suggested that the mutation resulted from slipped mispairing during DNA replication. In a patient with typical PSACH, {5:Briggs et al. (1998)} identified heterozygosity for a 3-bp deletion (delGAC 1139-1147) in the COMP gene. Chondrocytes from the patient showed the characteristic lamellar inclusions of the rough endoplasmic reticulum observed in PSACH. {3:Briggs and Chapman (2002)} reviewed mutations in the COMP gene resulting in PSACH and, using nucleotide numbering from the start site of translation, designated this nucleotide change as 1114-1122 delGAC and the corresponding protein change as delD(372-374). mutations COMP, 3-BP DEL, (GAC)2 number 18 clinvarAccessions RCV000029149;;1 prefix * titles alternativeTitles THROMBOSPONDIN V; THBS5 preferredTitle CARTILAGE OLIGOMERIC MATRIX PROTEIN; COMP textSectionList textSection textSectionTitle Description textSectionContent COMP is a pentameric extracellular matrix protein that catalyzes the assembly of collagens and promotes formation of well-defined fibrils ({10:Halasz et al., 2007}). textSectionName description textSectionTitle Cloning textSectionContent Cartilage oligomeric matrix protein is a 524-kD protein that is expressed at high levels in the territorial matrix of chondrocytes. The sequences of rat and bovine COMP indicate that it is a member of the thrombospondin gene family ({25:Newton et al., 1994}). {24:Maddox et al. (2000)} reported that 5 identical COMP molecules associate via their N-terminal coiled-coil domains into a bouquet-like structure with 5 flexible arms. The flexible arms contain 4 EGF-like repeats, followed by 8 thrombospondin (see {188060}) type 3 repeats, and a large C-terminal globular domain. The type 3 repeats are predicted to bind calcium. {18:Kleerekoper et al. (2002)} stated that full-length human COMP contains 757 amino acids. {10:Halasz et al. (2007)} stated that in young cartilage COMP is primarily identified close to chondrocytes, whereas in adult cartilage it is found in the interterritorial region. Using immunohistochemical analysis, {1:Agarwal et al. (2012)} detected COMP expression in normal human skin. COMP localized in a continuous linear pattern mainly at the superficial papillary dermis, just below epidermal keratinocytes. Much lower expression was detected in reticular dermis. Quantitative real-time RT-PCR detected abundant COMP expression in extracts of separated dermis and in cultured primary dermal fibroblasts, but not in epidermal extracts or cultured HaCaT keratinocytes. Electron microscopy revealed that COMP localized subepidermally in clusters that overlapped with, but were not limited to, anchoring plaques. In skin, COMP expression partly colocalized with collagens XII (COL12A1; {120320}) and XIV (COL14A1; {120324}). textSectionName cloning textSectionTitle Gene Function textSectionContent {31:Thur et al. (2001)} expressed recombinant wildtype rat COMP that showed structural and functional properties identical to COMP isolated from cartilage. The fragment encompassing the 8 type-3 repeats bound 14 calcium ions with moderate affinity and high cooperativity and presumably formed 1 large disulfide-bonded folding unit. A recombinant PSACH mutant COMP in which asp469 was deleted and a MED mutant COMP in which asp361 was substituted by tyr (D361Y) were both secreted into the cell culture medium of human cells. The number of bound calcium ions was reduced. In addition to collagen I (see {120150}) and II (see {120140}), collagen IX normally binds to COMP with high affinity; the PSACH and MED mutations reduced the binding of these 3 collagens and resulted in altered zinc dependence. These interactions may explain why MED can also be caused by mutations in collagen IX genes (COL9A2, {120260} and COL9A3, {120270}). Using rotary shadowing electron microscopy and immobilized proteins, {13:Holden et al. (2001)} characterized the interaction between purified chick sternal cartilage type IX collagen (see COL9A1; {120210}) and purified fetal bovine Comp or the isolated human COMP C-terminal domain. They identified a collagen-binding site between residues 579 and 595 of the C-terminal domain of COMP that bound each of 4 noncollagenous domains in collagen IX. Using a yeast 2-hybrid screen, {19:Liu et al. (2006)} found that human COMP interacted with the extracellular metalloprotease Adamts7 ({605009}) in a rat brain cDNA library. The interaction was confirmed by protein pull-down and immunoprecipitation experiments. Domain analysis revealed that the C-terminal thrombospondin repeats of Adamts7 interacted with the EGF-like domain of COMP. Both full-length Adamts7 and the isolated catalytic domain (amino acids 217 to 468) of human ADAMTS7 digested COMP in a dose- and time-dependent manner. {10:Halasz et al. (2007)} stated that pentameric bovine Comp binds via each C-terminal globule domain to 1 of 4 sites on collagens I (see {120150}) and II (see {120140}). They found that monomeric recombinant bovine Comp lacking the N-terminal coiled-coil domain showed weak fibril formation with collagens I and II. Fibril formation was much faster in the presence of purified pentameric Comp. Comp interacted primarily with free collagen I and II molecules, bringing several molecules to close proximity and promoting their assembly. Comp was not associated with mature fibrils and dissociates from the collagen molecules or their early assemblies. {10:Halasz et al. (2007)} concluded that COMP catalyzes fibril formation by promoting early association of collagen molecules, leading to increased rate of fibrillogenesis. By characterizing mouse constructs expressed in human HEK293-EBNA cells, {1:Agarwal et al. (2012)} found that pentameric Comp bound collagens XII and XIV. In both cases, Comp bound to C-terminal collagenous domains of the collagens, but not to their large noncollagenous-3 domains. textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {4:Briggs et al. (1995)} demonstrated that the COMP gene contains 19 exons. Exons 4-19, which encode the EGF-like (type II) repeats, calmodulin-like (type III) repeats (CLRs), and the C-terminal domain, correspond in sequence and intron location to the thrombospondin genes, whereas exons 1-3 are unique to COMP. They presented a table giving the gene structure of COMP in terms of exon size, intron location, and nucleotide sequence of the splice donor and splice acceptor regions of all exon/intron junctions. textSectionName geneStructure textSectionTitle Mapping textSectionContent By Southern blot analysis of a somatic cell hybrid DNA panel and by isotopic in situ hybridization, {25:Newton et al. (1994)} mapped the human COMP gene to 19p13.1. {25:Newton et al. (1994)} mapped the murine Comp gene to the central region of mouse chromosome 8 by use of an interspecific backcross mapping panel. textSectionName mapping textSectionTitle Evolution textSectionContent {25:Newton et al. (1994)} reported a phylogenetic analysis indicating that the COMP gene and a precursor of the thrombospondin-3 ({188062}) and thrombospondin-4 ({600715}) genes were produced by a gene duplication that occurred 750 million years ago. textSectionName evolution textSectionTitle Molecular Genetics textSectionContent COMP was a candidate gene for the site of the mutation in both pseudoachondroplasia (PSACH; {177170}) and one form of multiple epiphyseal dysplasia (MED) (EDM1; {132400}) because both disorders map to 19p13.1-p12. {12:Hecht et al. (1995)} used single-strand conformation polymorphism (SSCP) analysis and nucleotide sequencing to identify COMP mutations in 8 familial and isolated PSACH cases. All mutations involved either a 1-bp change or a 3-bp deletion in the same exon. In 6 patients, 6 mutation events either deleted or changed well-conserved aspartic acid residues within the calcium-binding type-3 repeats (see {600310.0001} and {600310.0004}). In the process of determining the COMP genomic sequence, {4:Briggs et al. (1995)} identified a polymorphic (GAAA)12 repeat at the 3-prime end of an Alu element within intron 9. Using this marker for study of linkage in 2 large families previously used to establish linkage to chromosome 19 of PSACH/EDM1, they found 2 individuals, 1 from each family, who were not recombinant at the COMP marker. The 2 had been shown previously to be recombinant at flanking markers used to define the 800-kb PSACH/EDM1 interval. {4:Briggs et al. (1995)} also demonstrated specific mutations in the COMP gene in 2 patients with pseudoachondroplasia ({600310.0006} and {600310.0018}) and 1 patient with the Fairbank form of MED ({600310.0005}). Thus, the allelic nature of these 2 disorders was established. {29:Susic et al. (1997)} found heterozygosity for a 12-bp deletion in exon 10 of the COMP gene in a child with a mild form of pseudoachondroplasia. A child with the Fairbank type of multiple epiphyseal dysplasia was heterozygous for a cys371-to-ser amino acid substitution in the fourth CLR. These findings were thought to support the proposal that deletions and insertions within the calmodulin-like domain produce pseudoachondroplasia, whereas amino acid substitutions within this domain may produce either pseudoachondroplasia or MED. {5:Briggs et al. (1998)} reported identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single amino acid deletions or substitutions, all in the region of the COMP gene encoding the CLR elements, were identified in patients with moderate to severe PSACH (see, e.g., {600310.0004} and {600310.0018}). They also identified within this domain a missense mutation that produced MED of the Fairbank type. In 2 families, one with mild PSACH and the other with a form of MED, they identified different substitutions for a residue in the C-terminal globular region of COMP. Both the clinical presentations of these 2 families and the identification of mutations in the COMP gene provided evidence of phenotypic overlap between PSACH and MED. In 12 patients with PSACH, {6:Deere et al. (1998)} identified 12 mutations in the COMP gene, including 10 novel mutations. The site of the mutations emphasized the importance of the calcium-binding domains and the globular domain to the function of COMP. {7:Deere et al. (1999)} reported 9 novel mutations in COMP causing PSACH and EDM1. These included 4 mutations in exons 13C and 14 where no previous mutations had been identified, a case of PSACH resulting from an expansion of the 5 aspartates in exon 17B, and a PSACH family with somatic/germline mosaicism. {16:Ikegawa et al. (1998)} screened the COMP gene in 15 patients with PSACH or MED by direct sequencing of PCR products from genomic DNA. They identified 10 mutations involving conserved residues among the 8 CLRs of the gene product: 7 were missense mutations in exons 9, 10, 11, 13 or 14, and the other 3 resulted from deletion of 1 of the 5 GAC repeats in exon 13 ({600310.0004}). They found that the GAC repeats in the seventh CLR in exon 13 represent a hotspot for mutation and that mutations in the seventh calmodulin-like repeat produce severe PSACH phenotypes whereas mutations elsewhere in the gene exhibit mild PSACH or MED phenotypes. They suggested that these genotype/phenotype correlations may facilitate molecular diagnosis and classification of PSACH and MED, and provide insight into the relationship between structure and function of the COMP gene product. {8:Delot et al. (1999)} stated that about one-third of patients with PSACH are heterozygous for deletion of 1 codon within a very short triplet repeat, (GAC)5, which encodes 5 consecutive aspartic acid residues within the calmodulin-like region of the COMP protein ({600310.0004}). {8:Delot et al. (1999)} identified 2 expansion mutations in this repeat: an MED patient carrying a (GAC)6 allele ({600310.0012}), and a PSACH patient carrying a (GAC)7 allele ({600310.0011}). These were among the shortest disease-causing triplet repeat expansion mutations described to that time, and the first identified in a GAC repeat. A unique feature of this sequence was that expansion as well as shortening of the repeat could cause the same disease. In cartilage, both patients had the rough endoplasmic reticulum inclusions in chondrocytes. These inclusions were also present in tendon tissue and could be reproduced in cultured tendon cells, suggesting that the pathophysiology of the disease is similar in both cartilage and tendon. Another example of disease production by expansion of a short trinucleotide repeat has been observed in the case of the polyadenylate-binding protein-2 gene (PABP2; {602279}), which is mutant in oculopharyngeal muscular dystrophy (OPMD; {164300}). In OPMD, the common (GCG)6 wildtype sequence was found to be expanded to pathologic (GCG)7-13 alleles. Late-onset mild MED is occasionally indistinguishable from common osteoarthritis ({165720}). Furthermore, a mutation in the C terminus of the COMP gene was reported by {5:Briggs et al. (1998)} as producing an individual of normal height with skeletal abnormalities that included early osteoarthritis. For these reasons, {21:Mabuchi et al. (2001)} hypothesized that osteoarthritis as a common disorder may be at the mild end of the phenotypic gradation produced by COMP mutations. They ascertained the sequences of the exons and exon-intron boundaries and identified 16 polymorphisms in the COMP gene. Using 6 polymorphisms spanning the entire COMP gene, they examined the association of this gene in Japanese patients with osteoarthritis of the knee and hip joints. Genotype and allele frequencies of the polymorphisms were not significantly different between osteoarthritis and control groups, and there was no significant difference in haplotypes. {9:Dinser et al. (2002)} developed a cell culture model of pseudoachondroplasia by expressing mutant COMP in bovine primary chondrocytes. They showed that mutant COMP exerts its deleterious effects through both intra- and extracellular pathogenic pathways. Overexpression of mutant COMP led to a dose-dependent decrease in cellular viability. The secretion of mutant COMP was markedly delayed, presumably due to a prolonged association with chaperones in the endoplasmic reticulum. The extracellular matrix lacked organized collagen fibers and showed amorphous aggregates formed by mutant COMP. Thus, pseudoachondroplasia appeared to be an endoplasmic reticulum storage disease, most likely caused by improper folding of mutant COMP. The growth failure of patients with pseudoachondroplasia may be explained by an increased cell death of growth-plate chondrocytes. Dominant interference of the mutant protein with collagen fiber assembly could contribute to the observed failure of the extracellular matrix of cartilage and tendons. {22:Mabuchi et al. (2003)} reported the identification of 9 novel and 3 recurrent COMP mutations in PSACH and MED patients. These included 2 novel types of mutations: a deletion spanning an exon-intron junction causing an exon deletion ({600310.0015}), and a frameshift mutation resulting in a truncation of the C-terminal domain ({600310.0016}). The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the CLR region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs and elsewhere in the COMP gene. Patients carrying mutations within the 5-aspartate repeat (amino acids 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations. {27:Song et al. (2003)} identified mutations in the COMP gene in 9 of 9 Korean patients with PSACH and in 3 of 5 Korean patients with MED. Three of the 8 mutations identified were novel. {17:Jakkula et al. (2003)} identified a mutation in the COMP gene ({600310.0017}) in patients presenting with muscular weakness, a moderate rise in creatine kinase and MED beginning in the knee joints. They suggested that the clinical and radiographic overlap between collagen IX-MED and COMP-MED pointed to a common supramolecular complex pathogenesis. Genetic diagnosis of the COMP-related skeletal dysplasias pseudoachondroplasia and multiple epiphyseal dysplasia is difficult because COMP mutations are scattered throughout the gene and 5 additional disease genes for multiple epiphyseal dysplasia exist. {23:Mabuchi et al. (2004)} presented evidence that plasma COMP levels are significantly decreased in patients with COMP mutations compared with controls (p less than 0.0001). In addition, plasma COMP levels were significantly decreased in MED patients carrying mutations in COMP relative to those who lacked COMP mutations (p = 0.001). These results indicated that measuring the level of circulating COMP may be an easier, more rapid, and cost-efficient method for diagnosing PSACH and particularly for diagnosing MED. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent To study the role of COMP in vivo, {30:Svensson et al. (2002)} generated COMP-null mice and found that they showed no anatomic, histologic, or ultrastructural abnormalities associated with the pseudoachondroplasia ({177170}) or multiple epiphyseal dysplasia ({132400}) phenotypes. Northern blot and immunohistochemical analyses of cartilage indicated that the lack of COMP was not compensated for by any other member of the thrombospondin family. {30:Svensson et al. (2002)} reported that the phenotype in PSACH and MED is caused not by the reduced amount of COMP but by some other mechanism, such as folding defects or extracellular assembly abnormalities due to dysfunctional mutated COMP. PSACH and MED patients often have a mild myopathy characterized by mildly increased plasma creatine kinase levels, a variation in myofiber size and/or small atrophic fibers. {26:Pirog et al. (2010)} studied skeletal muscle, tendon, and ligament in a mouse model of mild PSACH harboring a T585M mutation. T585M-mutant mice exhibited a progressive muscle weakness associated with an increased number of muscle fibers with central nuclei at the perimysium and at the myotendinous junction. Collagen fibril diameters in the mutant tendons and ligaments were thicker, and tendons became more lax in cyclic strain tests. {26:Pirog et al. (2010)} hypothesized that the myopathy in PSACH-MED may originate from underlying tendon and ligament pathology that may be a direct result of abnormalities in collagen fibril architecture. Using homologous recombination, {28:Suleman et al. (2012)} generated a knock-in mouse model carrying the common D469del mutation in the COMP gene ({600310.0004}), which is found in approximately one-third of patients with PSACH. In contrast to the human PSACH phenotype, which is a dominant disease, both copies of the mutant allele were required for the mice to develop a quantifiable chondrodysplasia phenotype. Mutant animals were normal at birth but grew slower than their wildtype littermates and developed short-limb dwarfism. In growth plates of mutant mice, chondrocyte columns were reduced in number and poorly organized, and mutant COMP was retained within the endoplasmic reticulum of cells. Chondrocyte proliferation was reduced and apoptosis was both increased and spatially dysregulated. Unlike earlier studies, {28:Suleman et al. (2012)} observed no evidence of an unfolded protein response in this mouse model of PSACH. In contrast, microarray analysis identified expression changes in groups of genes implicated in oxidative stress, cell cycle regulation, and apoptosis, consistent with the chondrocyte pathology. {28:Suleman et al. (2012)} suggested that a novel form of chondrocyte stress triggered by the expression of mutant COMP is central to the pathogenesis of PSACH. textSectionName animalModel geneMapExists true editHistory alopez : 10/17/2013 alopez : 10/17/2013 alopez : 10/17/2013 alopez : 10/17/2013 alopez : 10/14/2013 carol : 4/18/2013 carol : 7/11/2012 wwang : 11/18/2010 terry : 11/12/2010 ckniffin : 10/16/2007 ckniffin : 10/15/2007 alopez : 1/28/2005 alopez : 1/28/2005 wwang : 1/18/2005 wwang : 1/14/2005 wwang : 1/12/2005 terry : 1/11/2005 carol : 10/8/2004 carol : 4/29/2004 carol : 4/7/2004 carol : 4/7/2004 terry : 3/30/2004 mgross : 8/21/2003 terry : 8/19/2003 carol : 1/9/2003 tkritzer : 1/6/2003 terry : 12/30/2002 terry : 12/30/2002 tkritzer : 12/18/2002 terry : 12/13/2002 carol : 7/10/2002 alopez : 6/10/2002 joanna : 6/7/2002 mcapotos : 12/17/2001 mcapotos : 12/7/2001 mcapotos : 9/27/2001 mcapotos : 9/25/2001 terry : 9/20/2001 mcapotos : 4/24/2001 mcapotos : 4/18/2001 terry : 4/12/2001 carol : 10/1/1999 mgross : 2/25/1999 mgross : 2/22/1999 terry : 2/18/1999 carol : 2/1/1999 carol : 2/1/1999 terry : 1/20/1999 carol : 1/20/1999 terry : 1/15/1999 carol : 4/18/1998 terry : 3/27/1998 jenny : 6/23/1997 mark : 6/18/1997 jenny : 3/27/1997 terry : 3/21/1997 jamie : 1/29/1997 mimadm : 9/23/1995 mark : 6/30/1995 carol : 1/18/1995 dateCreated Wed, 18 Jan 1995 03:00:00 EST creationDate Victor A. McKusick : 1/18/1995 epochUpdated 1381993200 dateUpdated Thu, 17 Oct 2013 03:00:00 EDT referenceList reference articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=22573329 publisherName HighWire Press title Collagen XII and XIV, new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. mimNumber 600310 referenceNumber 1 publisherAbbreviation HighWire pubmedID 22573329 source J. Biol. Chem. 287: 22549-22559, 2012. authors Agarwal, P., Zwolanek, D., Keene, D. R., Schulz, J.-N., Blumbach, K., Heinegard, D., Zaucke, F., Paulsson, M., Krieg, T., Koch, M., Eckes, B. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19970211)68:4<396::AID-AJMG4>3.0.CO;2-K publisherName John Wiley & Sons, Inc. title Multiple epiphyseal dysplasia, Ribbing type: a novel point mutation in the COMP gene in a South African family. mimNumber 600310 referenceNumber 2 publisherAbbreviation Wiley pubmedID 9021009 source Am. J. Med. Genet. 68: 396-400, 1997. Note: Erratum: Am. J. Med. Genet. 71: 494 only, 1997. authors Ballo, R., Briggs, M. D., Cohn, D. H., Knowlton, R. G., Beighton, P. H., Ramesar, R. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.10066 publisherName John Wiley & Sons, Inc. title Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. mimNumber 600310 referenceNumber 3 publisherAbbreviation Wiley pubmedID 11968079 source Hum. Mutat. 19: 465-478, 2002. authors Briggs, M. D., Chapman, K. L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng0795-330 publisherName Nature Publishing Group title Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. mimNumber 600310 referenceNumber 4 publisherAbbreviation NPG pubmedID 7670472 source Nature Genet. 10: 330-336, 1995. authors Briggs, M. D., Hoffman, S. M. G., King, L. M., Olsen, A. S., Mohrenweiser, H., Leroy, J. G., Mortier, G. R., Rimoin, D. L., Lachman, R. S., Gaines, E. S., Cekleniak, J. A., Knowlton, R. G., Cohn, D. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63496-X publisherName Elsevier Science title Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. mimNumber 600310 referenceNumber 5 publisherAbbreviation ES pubmedID 9463320 source Am. J. Hum. Genet. 62: 311-319, 1998. authors Briggs, M. D., Mortier, G. R., Cole, W. G., King, L. M., Golik, S. S., Bonaventure, J., Nuytinck, L., De Paepe, A., Leroy, J. G., Biesecker, L., Lipson, M., Wilcox, W. R., Lachman, R. S., Rimoin, D. L., Knowlton, R. G., Cohn, D. H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19981228)80:5<510::AID-AJMG14>3.0.CO;2-F publisherName John Wiley & Sons, Inc. title Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia. mimNumber 600310 referenceNumber 6 publisherAbbreviation Wiley pubmedID 9880218 source Am. J. Med. Genet. 80: 510-513, 1998. authors Deere, M., Sanford, T., Ferguson, H. L., Daniels, K., Hecht, J. T. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19990827)85:5<486::AID-AJMG10>3.0.CO;2-O publisherName John Wiley & Sons, Inc. title Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. mimNumber 600310 referenceNumber 7 publisherAbbreviation Wiley pubmedID 10405447 source Am. J. Med. Genet. 85: 486-490, 1999. authors Deere, M., Sanford, T., Francomano, C. A., Daniels, K., Hecht, J. T. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9887340 publisherName HighWire Press title Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene. mimNumber 600310 referenceNumber 8 publisherAbbreviation HighWire pubmedID 9887340 source Hum. Molec. Genet. 8: 123-128, 1999. authors Delot, E., King, L. M., Briggs, M. D., Wilcox, W. R., Cohn, D. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI14386 publisherName Journal of Clinical Investigation title Pseudoachondroplasia is caused through both intra- and extracellular pathogenic pathways. mimNumber 600310 referenceNumber 9 publisherAbbreviation JCI pubmedID 12189245 source J. Clin. Invest. 110: 505-513, 2002. authors Dinser, R., Zaucke, F., Kreppel, F., Hultenby, K., Kochanek, S., Paulsson, M., Maurer, P. pubmedImages false publisherUrl http://www.jci.org articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17716974 publisherName HighWire Press title COMP acts as a catalyst in collagen fibrillogenesis. mimNumber 600310 referenceNumber 10 publisherAbbreviation HighWire pubmedID 17716974 source J. Biol. Chem. 282: 31166-31173, 2007. authors Halasz, K., Kassner, A., Morgelin, M., Heinegard, D. pubmedImages false publisherUrl http://highwire.stanford.edu source Birth Defects Orig. Art. Ser. V(4): 254-259, 1969. mimNumber 600310 authors Hall, J. G., Dorst, J. P. title Pseudoachondroplastic SED, recessive Maroteaux-Lamy type. referenceNumber 11 articleUrl http://dx.doi.org/10.1038/ng0795-325 publisherName Nature Publishing Group title Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. mimNumber 600310 referenceNumber 12 publisherAbbreviation NPG pubmedID 7670471 source Nature Genet. 10: 325-329, 1995. authors Hecht, J. T., Nelson, L. D., Crowder, E., Wang, Y., Elder, F. F. B., Harrison, W. R., Francomano, C. A., Prange, C. K., Lennon, G. G., Deere, M., Lawler, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11087755 publisherName HighWire Press title Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. mimNumber 600310 referenceNumber 13 publisherAbbreviation HighWire pubmedID 11087755 source J. Biol. Chem. 276: 6046-6055, 2001. authors Holden, P., Meadows, R. S., Chapman, K. L., Grant, M. E., Kadler, K. E., Briggs, M. D. pubmedImages false publisherUrl http://highwire.stanford.edu source Tokyo, Japan 11/30/1998. mimNumber 600310 authors Ikegawa, S. title Personal Communication. referenceNumber 14 articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19980605)77:5<356::AID-AJMG3>3.0.CO;2-L publisherName John Wiley & Sons, Inc. title Pseudoachondroplasia with de novo deletion [del(11)(q21q22.2)]. mimNumber 600310 referenceNumber 15 publisherAbbreviation Wiley pubmedID 9632164 source Am. J. Med. Genet. 77: 356-359, 1998. authors Ikegawa, S., Ohashi, H., Hosoda, F., Fukushima, Y., Ohki, M., Nakamura, Y. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://link.springer.de/link/service/journals/00439/bibs/8103006/81030633.htm publisherName Springer title Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple epiphyseal dysplasia. mimNumber 600310 referenceNumber 16 publisherAbbreviation Springer pubmedID 9921895 source Hum. Genet. 103: 633-638, 1998. authors Ikegawa, S., Ohashi, H., Nishimura, G., Kim, K. C., Sannohe, A., Kimizuka, M., Fukushima, Y., Nagai, T., Nakamura, Y. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=14684695 publisherName HighWire Press title A recurrent R718W mutation in COMP results in multiple epiphyseal dysplasia with mild myopathy: clinical and pathogenetic overlap with collagen IX mutations. mimNumber 600310 referenceNumber 17 publisherAbbreviation HighWire pubmedID 14684695 source J. Med. Genet. 40: 942-948, 2003. authors Jakkula, E., Lohiniva, J., Capone, A., Bonafe, L., Marti, M., Schuster, V., Giedion, A., Eich, G., Boltshauser, E., Ala-Kokko, L., Superti-Furga, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11782471 publisherName HighWire Press title Disease-causing mutations in cartilage oligomeric matrix protein cause an unstructured Ca(2+) binding domain. mimNumber 600310 referenceNumber 18 publisherAbbreviation HighWire pubmedID 11782471 source J. Biol. Chem. 277: 10581-10589, 2002. authors Kleerekoper, Q., Hecht, J. T., Putkey, J. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=16585064 publisherName HighWire Press title ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. mimNumber 600310 referenceNumber 19 publisherAbbreviation HighWire pubmedID 16585064 source FASEB J. 20: 988-990, 2006. authors Liu, C., Kong, W., Ilalov, K., Yu, S., Xu, K., Prazak, L., Fajardo, M., Sehgal, B., Di Cesare, P. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.10067 publisherName John Wiley & Sons, Inc. title Novel mutation in exon 18 of the cartilage oligomeric matrix protein gene causes a severe pseudoachondroplasia. mimNumber 600310 referenceNumber 20 publisherAbbreviation Wiley pubmedID 11746044 source Am. J. Med. Genet. 104: 135-139, 2001. authors Mabuchi, A., Haga, N., Ikeda, T., Manabe, N., Ohashi, H., Takatori, Y., Nakamura, K., Ikegawa, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Identification of sequence polymorphisms of the COMP (cartilage oligomeric matrix protein) gene and association study in osteoarthrosis of the knee and hip joints. mimNumber 600310 referenceNumber 21 pubmedID 11501943 source J. Hum. Genet. 46: 456-462, 2001. authors Mabuchi, A., Ikeda, T., Fukuda, A., Koshizuka, Y., Hiraoka, H., Miyoshi, K., Haga, N., Kawaguchi, H., Kawakami, A., Yamamoto, S., Takatori, Y., Nakamura, K., Ikegawa, S. pubmedImages false articleUrl http://dx.doi.org/10.1007/s00439-002-0845-9 publisherName Springer title Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia. mimNumber 600310 referenceNumber 22 publisherAbbreviation Springer pubmedID 12483304 source Hum. Genet. 112: 84-90, 2003. authors Mabuchi, A., Manabe, N., Haga, N., Kitoh, H., Ikeda, T., Kawaji, H., Tamai, K., Hamada, J., Nakamura, S., Brunetti-Pierri, N., Kimizuka, M., Takatori, Y., Nakamura, K., Nishimura, G., Ohashi, H., Ikegawa, S. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.30164 publisherName John Wiley & Sons, Inc. title Circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations. mimNumber 600310 referenceNumber 23 publisherAbbreviation Wiley pubmedID 15266613 source Am. J. Med. Genet. 129A: 35-38, 2004. authors Mabuchi, A., Momohara, S., Ohashi, H., Takatori, Y., Haga, N., Nishimura, G., Ikegawa, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10753957 publisherName HighWire Press title A cartilage oligomeric matrix protein mutation associated with pseudoachondroplasia changes the structural and functional properties of the type 3 domain. mimNumber 600310 referenceNumber 24 publisherAbbreviation HighWire pubmedID 10753957 source J. Biol. Chem. 275: 11412-11417, 2000. authors Maddox, B. K., Mokashi, A., Keene, D. R., Bachinger, H. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(84)71649-1 publisherName Elsevier Science title Characterization of human and mouse cartilage oligomeric matrix protein. mimNumber 600310 referenceNumber 25 publisherAbbreviation ES pubmedID 7713493 source Genomics 24: 435-439, 1994. authors Newton, G., Weremowicz, S., Morton, C. C., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Lawler, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19808781 publisherName HighWire Press title A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. mimNumber 600310 referenceNumber 26 publisherAbbreviation HighWire pubmedID 19808781 source Hum. Molec. Genet. 19: 52-64, 2010. authors Pirog, K. A., Jaka, O., Katakura, Y., Meadows, R. S., Kadler, K. E., Boot-Handford, R. P., Briggs, M. D. pubmedImages false publisherUrl http://highwire.stanford.edu title Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. mimNumber 600310 referenceNumber 27 pubmedID 12768438 source J. Hum. Genet. 48: 222-225, 2003. authors Song, H.-R., Lee, K.-S., Li, Q.-W., Koo, S. K., Jung, S.-C. pubmedImages false articleUrl http://dx.doi.org/10.1002/humu.21631 publisherName John Wiley & Sons, Inc. title A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. mimNumber 600310 referenceNumber 28 publisherAbbreviation Wiley pubmedID 22006726 source Hum. Mutat. 33: 218-231, 2012. authors Suleman, F., Gualeni, B., Gregson, H. J., Leighton, M. P., Pirog, K. A., Edwards, S., Holden, P., Boot-Handford, R. P., Briggs, M. D. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Multiple epiphyseal dysplasia and pseudoachondroplasia due to novel mutations in the calmodulin-like repeats of cartilage oligomeric matrix protein. mimNumber 600310 referenceNumber 29 pubmedID 9184241 source Clin. Genet. 51: 219-224, 1997. authors Susic, S., McGrory, J., Ahier, J., Cole, W. G. pubmedImages false articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=12024046 publisherName HighWire Press title Cartilage oligomeric matrix protein-deficient mice have normal skeletal development. mimNumber 600310 referenceNumber 30 publisherAbbreviation HighWire pubmedID 12024046 source Molec. Cell. Biol. 22: 4366-4371, 2002. authors Svensson, L., Aszodi, A., Heinegard, D., Hunziker, E. B., Reinholt, F. P., Fassler, R., Oldberg, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11084047 publisherName HighWire Press title Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. mimNumber 600310 referenceNumber 31 publisherAbbreviation HighWire pubmedID 11084047 source J. Biol. Chem. 276: 6083-6092, 2001. authors Thur, J., Rosenberg, K., Nitsche, D. P., Pihlajamaa, T., Ala-Kokko, L., Heinegard, D., Paulsson, M., Maurer, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.10062 publisherName John Wiley & Sons, Inc. title Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. mimNumber 600310 referenceNumber 32 publisherAbbreviation Wiley pubmedID 11746045 source Am. J. Med. Genet. 104: 140-146, 2001. authors Unger, S., Korkko, J., Krakow, D., Lachman, R. S., Rimoin, D. L., Cohn, D. H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ externalLinks cmgGene false mgiHumanDisease false hprdIDs 02632 nbkIDs NBK1487;;Pseudoachondroplasia;;;NBK1123;;Multiple Epiphyseal Dysplasia, Dominant refSeqAccessionIDs NG_007070.1 uniGenes Hs.1584 approvedGeneSymbols COMP nextGxDx true flybaseIDs FBgn0031850 dermAtlas false umlsIDs C1456376 gtr true geneIDs 1311 swissProtIDs P49747 zfinIDs ZDB-GENE-060606-1 ensemblIDs ENSG00000105664,ENST00000222271 geneTests true mgiIDs MGI:88469 ncbiReferenceSequences 530414509,40217842 genbankNucleotideSequences 194387575,22759998,124000270,2623749,194387545,71515761,158254621,123993232,511789621,1184518,27530065,1184516,10935632,84570076,62897992,602449,529606056,194383693,21707184,148140873,115527965 proteinSequences 209572601,22759999,124000271,194387546,2623750,194387576,158254622,123993233,119605141,1184519,119605143,27530066,62897993,40217843,1184517,119605142,84570077,194383694,602450,115527966 geneticsHomeReferenceIDs gene;;COMP;;COMP

entryList

entry status live allelicVariantExists true epochCreated 946454400 geneMap geneSymbols MLH3, HNPCC7 sequenceID 10155 phenotypeMapList phenotypeMap phenotypeMimNumber 614385 mimNumber 604395 phenotypeInheritance None phenotypicSeriesMimNumber 120435 phenotypeMappingKey 3 phenotype Colorectal cancer, hereditary nonpolyposis, type 7 phenotypeMappingKey 3 mimNumber 604395 phenotypeInheritance Autosomal dominant phenotype Colorectal cancer, somatic phenotypeMimNumber 114500 phenotypeMappingKey 3 mimNumber 604395 phenotypeInheritance None phenotype {Endometrial cancer, susceptibility to} phenotypeMimNumber 608089 chromosomeLocationStart 75480466 chromosomeSort 312 chromosomeSymbol 14 mimNumber 604395 geneInheritance None confidence C mappingMethod A geneName Mismatch repair gene MLH3 mouseMgiID MGI:1353455 mouseGeneSymbol Mlh3 computedCytoLocation 14q24.3 cytoLocation 14q24.3 transcript uc001xrd.1 chromosomeLocationEnd 75518234 chromosome 14 contributors Cassandra L. Kniffin - updated : 7/31/2009 George E. Tiller - updated : 6/18/2003 Victor A. McKusick - updated : 7/8/2002 Victor A. McKusick - updated : 10/2/2001 Victor A. McKusick - updated : 6/25/2001 clinicalSynopsisExists false mimNumber 604395 allelicVariantList allelicVariant status live name COLORECTAL CANCER, SOMATIC dbSnps rs587776622 text In a colorectal cancer ({114500}) sample that showed loss of heterozygosity at 14q24, {6:Lipkin et al. (2001)} identified a 2483G-T transversion that converted codon GAG (glu) to TAG (stop) in the MLH3 gene. mutations MLH3, 2483G-T number 1 clinvarAccessions RCV000005896;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs28937870 text This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7, has been reclassified based on the findings of {3:Korhonen et al. (2008)} and {9:Ou et al. (2009)}. {12:Wu et al. (2001)} identified a 70C-G transversion in exon 1 of the MLH3 gene, resulting in a missense gln24-to-glu (Q24E) amino acid change in a patient with HNPCC. There was no associated mutation found in MSH6 ({600678}). By in vitro functional expression studies, {9:Ou et al. (2009)} determined that the Q24E MLH3 variant was expressed normally, localized normally in the cell nucleus, and interacted normally with MLH1 ({120436}). In silico analysis suggested no damaging effect of the change. Independent studies by {3:Korhonen et al. (2008)} showed that the Q24E variant functioned normally and was able to complement mismatch repair defects in cell lines. {9:Ou et al. (2009)} concluded that there is no evidence to support a role for this variant in HNPCC, although a role for the variant in tumorigenesis cannot be fully excluded. mutations MLH3, GLN24GLU number 2 clinvarAccessions RCV000005897;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs28937871 text This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7, has been reclassified based on the findings of {9:Ou et al. (2009)}. {12:Wu et al. (2001)} identified a 1496A-G transition in exon 1 of the MLH3 gene, resulting in an asn499-to-ser (N499S) amino acid change, in a patient with HNPCC. By in vitro functional expression studies, {9:Ou et al. (2009)} determined that the N499S MLH3 variant was expressed normally, localized normally in the cell nucleus, and interacted normally with MLH1 ({120436}). In silico analysis suggested a possibly damaging effect of the change. {9:Ou et al. (2009)} concluded that there is no evidence to support a role for this variant in HNPCC, although a role for the variant in tumorigenesis cannot be fully excluded. mutations MLH3, ASN499SER number 3 clinvarAccessions RCV000005898;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs28756986 text This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7, has been reclassified based on the findings of {9:Ou et al. (2009)}. In 2 unrelated probands with HNPCC, {12:Wu et al. (2001)} found an 1870G-C transversion in exon 1 of the MLH3 gene, predicted to result in a glu624-to-gln (E624Q) amino acid change. Immunohistochemical analysis demonstrated the expression of MSH2 ({609309}), MLH1 (see {120436}), and MSH6 ({600678}) in 1 patient. {8:Liu et al. (2003)} identified the E624Q substitution in 1 patient with familial colorectal cancer. However, none of 6 other affected family members carried this variant, and it was found in 3.2% of controls. By in vitro functional expression studies, {9:Ou et al. (2009)} determined that the N499S MLH3 variant was expressed normally, localized normally in the cell nucleus, and interacted normally with MLH1 ({120436}). In silico analysis suggested no damaging effect of the change. {9:Ou et al. (2009)} concluded that there is no evidence to support a role for this variant in HNPCC, although a role for the variant in tumorigenesis cannot be fully excluded. mutations MLH3, GLU624GLN number 4 clinvarAccessions RCV000005899;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs28939071 text This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7, has been reclassified based on the findings of {9:Ou et al. (2009)} and {3:Korhonen et al. (2008)}. In 2 probands with HNPCC, {12:Wu et al. (2001)} identified a heterozygous a 4351G-A transition in exon 12 of the MLH3 gene, predicted to result in a glu1451-to-lys (E1451K) amino acid substitution. Both probands were also compound heterozygous for a mutation in the MSH6 gene (V878A; {600678.0006} and 650insT; {600678.0007}, respectively). {8:Liu et al. (2003)} identified the E1451K mutation in a patient with colorectal cancer and in her sister with endometrial cancer ({608089}). However, the mutation was not found in another sister with colorectal cancer and was not found in 90 control individuals. {2:Kim et al. (2007)} identified the E1451K variant in healthy Korean controls and concluded that it is a polymorphism in that population. By in vitro functional expression studies, {9:Ou et al. (2009)} determined that the E1451K MLH3 variant was expressed normally, localized normally in the cell nucleus, and interacted normally with MLH1 ({120436}). In silico analysis suggested no damaging effect of the change. Independent studies by {3:Korhonen et al. (2008)} showed that the E1451K variant functioned normally and was able to complement mismatch repair defects in cell lines. {9:Ou et al. (2009)} concluded that there is no evidence to support a role for this variant in HNPCC, although a role for the variant in tumorigenesis cannot be fully excluded. mutations MLH3, GLU1451LYS number 5 clinvarAccessions RCV000005902;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7 text In a patient with colorectal cancer (HNPCC7; {614385}), {8:Liu et al. (2003)} identified a 1-bp deletion (885delG) in exon 1 of the MLH3 gene, predicted to result in a frameshift and premature termination. The mutation was found in another family member with colorectal cancer, in 1 family member with endometrial cancer ({608089}), and in 1 of 3 unaffected relatives over the age of 75 years, indicating reduced penetrance. The mutation was not found in 96 controls. mutations MLH3, 1-BP DEL, 885G number 6 alternativeNames ENDOMETRIAL CANCER, INCLUDED clinvarAccessions RCV000005904;;1;;;RCV000005903;;1 status live name ENDOMETRIAL CANCER dbSnps rs28756990 text In a mother and daughter with endometrial cancer ({608089}), {8:Liu et al. (2003)} identified a heterozygous 2221G-T transversion in exon 1 of the MLH3 gene, resulting in a val741-to-phe (V741F) substitution. An unaffected aunt, over the age of 80 years, also carried the mutation, indicating reduced penetrance. The mutation was not found in 95 controls. {2:Kim et al. (2007)} identified a V741F mutation in a 71-year-old man with colon cancer (HNPCC7; {614385}). His 2 sisters developed gastric cancer and breast cancer at ages 57 and 61, respectively. The authors suggested moderate penetrance for this variant. mutations MLH3, VAL741PHE number 7 alternativeNames COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7, INCLUDED clinvarAccessions RCV000005901;;1;;;RCV000005900;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 7 dbSnps rs121908439 text In 4 sibs with HNPCC (HNPCC7; {614385}) without microsatellite instability, {8:Liu et al. (2003)} identified a 3826T-C transition in exon 7 of the MLH3 gene, resulting in a trp1276-to-arg (W1276R) substitution. The mutation was inherited from the mother, who had gastric cancer. The mutation was not found in 96 controls. All 4 sibs also carried a mutation in the MSH2 gene ({609309}). {8:Liu et al. (2003)} suggested that the additive effect of these 2 mutations resulted in the phenotype. These findings were consistent with the hypothesis that low-penetrance additive risk alleles contribute to the risk of developing colorectal cancer. {7:Liu et al. (2006)} identified a W1276R substitution in 1 patient with colorectal cancer. However, 2 unaffected family members also carried the variant and 2 family members with esophageal cancer did not carry the mutation. mutations MLH3, TRP1276ARG number 8 clinvarAccessions RCV000005905;;1 prefix * titles preferredTitle MutL, E. COLI, HOMOLOG OF, 3; MLH3 textSectionList textSection textSectionTitle Cloning textSectionContent DNA mismatch repair (MMR) is important because of its role in maintaining genomic integrity and its association with hereditary nonpolyposis colon cancer (HNPCC; see {120435}). To identify new human mismatch repair proteins, {5:Lipkin et al. (2000)} probed nuclear extracts with the conserved C-terminal interaction domain of MLH1 ({120436}). They described the cloning and complete genomic sequence of MLH3, which encodes a DNA mismatch repair protein that interacts with MLH1. They found that MLH3 is more similar to mismatch repair proteins from yeast, plants, worms, and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibited microsatellite instability. textSectionName cloning textSectionTitle Gene Function textSectionContent To investigate whether MLH3 acts during meiotic recombination, ({10:Santucci-Darmanin et al. (2002)}) analyzed its expression in mammalian germ cells. The MLH3 gene was expressed in mouse meiotic cells and in human testis, and immunoprecipitation assays revealed that the MLH3 protein was found in mouse spermatocytes. The meiosis-specific MSH4 ({602105}) protein, known to participate in meiotic recombination, coimmunoprecipitated with MLH3 from mouse meiotic cell extracts. Two MLH3 protein isoforms potentially expressed in human testis (MLH3 and MLH3-delta-7) interacted in vitro with the MSH4 protein. The authors suggested that MLH3 is associated with MSH4 in mammalian meiotic cells, and that MLH3 may play a role in mammalian meiotic recombination. textSectionName geneFunction textSectionTitle Mapping textSectionContent By fluorescence in situ hybridization using mouse and human BACs, {5:Lipkin et al. (2000)} mapped the respective MLH3 genes to human 14q24.3 and mouse 12. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Somatic Mutation in Colorectal Cancer Malfunction of the mismatch repair system results in a mutator phenotype, which is manifested as microsatellite instability (MSI). MSI is often divided into 2 forms: MSI-high (MSI-H) and MSI-low (MSI-L), based quantitatively on the observed frequency of genomic mutations ({1:Boland et al., 1998}). {6:Lipkin et al. (2001)} screened 36 colon tumors and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). They found mutations in 8- and 9-bp polyadenine mononucleotide runs that resulted in frameshift. The 8-bp run extended from coding nucleotides 1747 to 1755; the 9-bp run extended from 2014 to 2021. In 4 of 6 tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in 2 of 12 microsatellite-stable (MSS) tumors with 14q24 loss of heterozygosity (see {604395.0001}). Screening of 60 probands with increased genetic risk factors for colorectal cancer susceptibility demonstrated no germline mutations of MLH3 and no mutations in other candidate genes. While the analyses did not exclude the existence of germline MLH3 mutations in some such patients, they suggested that they are at most uncommon. The finding of an appreciable frequency of somatic MLH3 mutations was considered consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hereditary Nonpolyposis Colorectal Cancer 7 {12:Wu et al. (2001)} investigated the possible role of MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC. They identified 10 different germline MLH3 variants, 1 frameshift and 9 missense mutations, in 12 patients suspected of HNPCC. In 3 of the 12 patients, a mutation was also found in MSH6 ({600678}). Eight of the 10 mutations were situated in exon 1, 1 was in exon 11, and 1 was in exon 12. The same group ({9:Ou et al., 2009}) found that all of the reported MLH3 variants were expressed normally, localized normally in the cell nucleus, and interacted normally with MLH1. {9:Ou et al. (2009)} concluded that there is no evidence to support a role for MLH3 variants in HNPCC, although a role for such variants in tumorigenesis cannot be fully excluded. {8:Liu et al. (2003)} identified 12 variants in the MLH3 gene (see, e.g., {604395.0005}-{604395.0008}) in 16 (23%) of 70 probands of families with colorectal cancer (HNPCC7; {614385}), some of whom had relatives with endometrial cancer. Most mutations showed reduced penetrance, suggesting that MLH3 is a low-risk gene and may work together with other factors in an additive manner. None of the tumors with MLH3 mutations showed microsatellite instability, indicating that MLH3 does not contribute to carcinogenesis through impaired DNA mismatch repair function. Esophageal Cancer In a cohort of patients with esophageal cancer ({133239}), {7:Liu et al. (2006)} found that while MLH3 is a high-risk gene with a reduced penetrance in some families, it acts as a low-risk gene in most families, and may work together with other genes in an accumulated manner. They concluded that MLH3 mutations may predispose to esophageal cancer in some families. Endometrial Cancer {11:Taylor et al. (2006)} analyzed the MLH3 gene in 57 women with endometrial cancer ({608089}). One patient had a germline variant (T942I) and loss of heterozygosity at the MLH3 locus in the tumor tissue. A germline heterozygous P844L polymorphism was found in 61% of patients. Somatic MLH3 mutations were identified in 3 of 57 tumors. Functional expression studies were not performed. {11:Taylor et al. (2006)} concluded that MLH3 mutations may play a role in a subset of endometrial cancers. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {5:Lipkin et al. (2000)} stated that mouse Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility-1 (Ccs1). Although {5:Lipkin et al. (2000)} were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumors from congenic Ccs1 mice exhibited microsatellite instability. Functional redundancy among Mlh3, Pms1 ({600258}), and Pms2 ({600259}) may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families. To assess the role of Mlh3 in mammalian meiosis, {4:Lipkin et al. (2002)} generated and characterized Mlh3 -/- mice. They showed that the null mice are viable but sterile. Mlh3 is required for Mlh1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid-pachynema stage of prophase I. Mlh3 -/- spermatocytes reached metaphase before succumbing to apoptosis, but oocytes failed to complete meiosis I after fertilization. The results showed that Mlh3 has an essential and distinct role in mammalian meiosis. textSectionName animalModel geneMapExists true editHistory carol : 10/09/2013 carol : 9/27/2013 alopez : 12/9/2011 carol : 11/24/2009 wwang : 9/2/2009 ckniffin : 7/31/2009 mgross : 4/15/2005 mgross : 4/15/2005 mgross : 4/14/2005 cwells : 6/18/2003 alopez : 8/1/2002 alopez : 7/8/2002 terry : 7/8/2002 alopez : 10/8/2001 terry : 10/2/2001 terry : 10/2/2001 mcapotos : 7/6/2001 mcapotos : 7/2/2001 terry : 6/25/2001 alopez : 12/30/1999 alopez : 12/29/1999 dateCreated Wed, 29 Dec 1999 03:00:00 EST creationDate Victor A. McKusick : 12/29/1999 epochUpdated 1381302000 dateUpdated Wed, 09 Oct 2013 03:00:00 EDT referenceList reference articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9823339 publisherName HighWire Press title A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. mimNumber 604395 referenceNumber 1 publisherAbbreviation HighWire pubmedID 9823339 source Cancer Res. 58: 5248-5257, 1998. authors Boland, C. R., Thibodeau, S. N., Hamilton, S. R., Sidransky, D., Eshleman, J. R., Burt, R. W., Meltzer, S. J., Rodriguez-Bigas, M. A., Fodde, R., Ranzani, G. N., Srivastava, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0165-4608(07)00256-7 publisherName Elsevier Science title MLH3 and EXO1 alterations in familial colorectal cancer patients not fulfilling Amsterdam criteria. (Letter) mimNumber 604395 referenceNumber 2 publisherAbbreviation ES pubmedID 17656264 source Cancer Genet. Cytogenet. 176: 172-174, 2007. authors Kim, J. C., Roh, S. A., Yoon, Y. S., Kim, H. C., Park, I. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/gcc.20581 publisherName John Wiley & Sons, Inc. title The first functional study of MLH3 mutations found in cancer patients. mimNumber 604395 referenceNumber 3 publisherAbbreviation Wiley pubmedID 18521850 source Genes Chromosomes Cancer 47: 803-809, 2008. authors Korhonen, M. K., Vuorenmaa, E., Nystrom, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng931 publisherName Nature Publishing Group title Meiotic arrest and aneuploidy in MLH3-deficient mice. mimNumber 604395 referenceNumber 4 publisherAbbreviation NPG pubmedID 12091911 source Nature Genet. 31: 385-390, 2002. authors Lipkin, S. M., Moens, P. B., Wang, V., Lenzi, M., Shanmugarajah, D., Gilgeous, A., Thomas, J., Cheng, J., Touchman, J. W., Green, E. D., Schwartzberg, P., Collins, F. S., Cohen, P. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/71643 publisherName Nature Publishing Group title MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. mimNumber 604395 referenceNumber 5 publisherAbbreviation NPG pubmedID 10615123 source Nature Genet. 24: 27-35, 2000. authors Lipkin, S. M., Wang, V., Jacoby, R., Banerjee-Basu, S., Baxevanis, A. D., Lynch, H. T., Elliott, R. M., Collins, F. S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/humu.1114 publisherName John Wiley & Sons, Inc. title Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: evidence for somatic mutation in colorectal cancers. mimNumber 604395 referenceNumber 6 publisherAbbreviation Wiley pubmedID 11317354 source Hum. Mutat. 17: 389-396, 2001. authors Lipkin, S. M., Wang, V., Stoler, D. L., Anderson, G. R., Kirsch, I., Hadley, D., Lynch, H. T., Collins, F. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.wjgnet.com/1007-9327/12/5281.asp publisherName World Journal of Gastroenterology title Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer. mimNumber 604395 referenceNumber 7 publisherAbbreviation WJG pubmedID 16981255 source World J. Gastroenterol. 12: 5281-5286, 2006. authors Liu, H.-X., Li, Y., Jiang, X.-D., Yin, H.-N., Zhang, L., Wang, Y., Yang, J. pubmedImages false publisherUrl http://www.wjgnet.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12702580 publisherName HighWire Press title The role of hMLH3 in familial colorectal cancer. mimNumber 604395 referenceNumber 8 publisherAbbreviation HighWire pubmedID 12702580 source Cancer Res. 63: 1894-1899, 2003. authors Liu, H.-X., Zhou, X.-L., Liu, T., Werelius, B., Lindmark, G., Dahl, N, Lindblom, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/gcc.20644 publisherName John Wiley & Sons, Inc. title Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome. mimNumber 604395 referenceNumber 9 publisherAbbreviation Wiley pubmedID 19156873 source Genes Chromosomes Cancer 48: 340-350, 2009. authors Ou, J., Rasmussen, M., Westers, H., Andersen, S. D., Jager, P. O., Kooi, K. A., Niessen, R. C., Eggen, B. J. L., Nielsen, F. C., Kleibeuker, J. H., Sijmons, R. H., Rasmussen, L. J., Hofstra, R. M. W. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12095912 publisherName HighWire Press title The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. mimNumber 604395 referenceNumber 10 publisherAbbreviation HighWire pubmedID 12095912 source Hum. Molec. Genet. 11: 1697-1706, 2002. authors {Santucci-Darmanin, S.}, Neyton, S., Lespinasse, F., Saunieres, A., Gaudray, P., Paquis-Flucklinger, V. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16885347 publisherName HighWire Press title MLH3 mutation in endometrial cancer. mimNumber 604395 referenceNumber 11 publisherAbbreviation HighWire pubmedID 16885347 source Cancer Res. 66: 7502-7508, 2006. authors Taylor, N. P., Powell, M. A., Gibb, R. K., Rader, J. S., Huettner, P. C., Thibodeau, S. N., Mutch, D. G., Goodfellow, P. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1001-137 publisherName Nature Publishing Group title A role for MLH3 in hereditary nonpolyposis colorectal cancer. mimNumber 604395 referenceNumber 12 publisherAbbreviation NPG pubmedID 11586295 source Nature Genet. 29: 137-138, 2001. authors Wu, Y., Berends, M. J. W., Sijmons, R. H., Mensink, R. G. J., Verlind, E., Kooi, K. A., van der Sluis, T., Kempinga, C., van der Zee, A. G. J., Hollema, H., Buys, C. H. C. M., Kleibeuker, J. H., Hofstra, R. M. W. pubmedImages false publisherUrl http://www.nature.com externalLinks mgiIDs MGI:1353455 mgiHumanDisease true ncbiReferenceSequences 530403516,530403518,530403513,91992159,530403514,530403511,91992161 refSeqAccessionIDs NG_008649.1 dermAtlas false hprdIDs 05094 swissProtIDs Q9UHC1 zfinIDs ZDB-GENE-060810-45 uniGenes Hs.436650 gtr true cmgGene false ensemblIDs ENSG00000119684,ENST00000355774 umlsIDs C1334511 genbankNucleotideSequences 6689927,219517972,511795843,148161456,21739375,511795844,62003156,887371,7209865,221042379,27824544,81285328,85567603,313883807,34783388,6689929,71518097,15214815,81216032,148161455,4680764,13539186 geneTests true approvedGeneSymbols MLH3 geneIDs 27030 proteinSequences 887372,578825729,317373417,34783389,313883808,91992162,91992160,221042380,530403517,530403519,7209866,530403512,530403515,62003157,6689930,85567604,6689928,119601617,4809339,119601618,119601619,119601620,119601621,578825722,21739376 nextGxDx true locusSpecificDBs http://www.insight-group.org/;;Hereditary Non-Polyposis Colorectal Cancer, HNPCC;;;http://databases.lovd.nl/genomed/home.php?select_db=MLH3;;Zhejiang University-Adinovo Center MLH3 Database

entryList

entry status live allelicVariantExists true epochCreated 930553200 geneMap geneSymbols RP1, ORP1 sequenceID 6391 phenotypeMapList phenotypeMap phenotypeMimNumber 180100 mimNumber 603937 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 268000 phenotypeMappingKey 3 phenotype Retinitis pigmentosa 1 chromosomeLocationStart 55528626 chromosomeSort 232 chromosomeSymbol 8 mimNumber 603937 geneInheritance None confidence C mappingMethod Fd, R, A geneName Oxygen-regulated photoreceptor protein-1 (retinitis pigmentosa-1) mouseMgiID MGI:1341105 mouseGeneSymbol Rp1 computedCytoLocation 8q12.1 cytoLocation 8q11-q13 transcript uc003xsd.1 chromosomeLocationEnd 55682523 chromosome 8 contributors Marla J. F. O'Neill - updated : 7/9/2012 Jane Kelly - updated : 11/20/2007 Marla J. F. O'Neill - updated : 6/20/2005 Victor A. McKusick - updated : 1/15/2004 Jane Kelly - updated : 7/9/2002 Victor A. McKusick - updated : 4/24/2001 Victor A. McKusick - updated : 10/25/1999 clinicalSynopsisExists false mimNumber 603937 allelicVariantList allelicVariant status live name RETINITIS PIGMENTOSA 1 dbSnps rs104894082 text In a patient with retinitis pigmentosa ({180100}), {11:Pierce et al. (1999)} found a C-to-T transition in exon 4 of the RP1 gene, resulting in a nonsense mutation, CGA (arg) to TGA (ter). This mutant allele, if expressed, would encode a protein of 676 amino acids, 1,480 less than the predicted wildtype RP1 protein. The mutation was first identified in the family in which {1:Blanton et al. (1991)} identified linkage to chromosome 8. The first member of the family studied was the offspring of 2 affected parents who were distantly related and presumed to carry the same RP1 mutation. The patient was found to be homozygous for the R677X mutation as was one of her sibs. Analysis of codon 677 in 17 other family members revealed that all of these affected members were heterozygotes. This family was also studied by {13:Sullivan et al. (1999)}, who reported that the homozygotes were unusually severely affected. {11:Pierce et al. (1999)} evaluated 242 patients with autosomal dominant RP from separate families across the United States and Canada for the R677X mutation. Patients with known mutations in other dominant RP genes, RHO ({180380}) or RDS (PRPH2; {179605}), were excluded from this analysis. They found 10 patients who were heterozygous for the R677X mutation. All 10 patients, who were examined at an age ranging from 35 to 49 years, with the mean age being 41.7 years, had findings typical of retinitis pigmentosa: night blindness as an early symptom, constricted visual fields, and funduscopic findings of attenuated vessels and intraretinal pigmentation. {11:Pierce et al. (1999)} reported that this mutation was present in approximately 3% of cases of autosomal dominant retinitis pigmentosa in North America. In affected members of an Australian RP1 family (family D), previously studied by {14:Xu et al. (1996)}, {13:Sullivan et al. (1999)} identified heterozygosity for the same R677X mutation in the RP1 gene as had been found in the UCLA-RP01 family. {13:Sullivan et al. (1999)} noted that 2 distinct haplotypes segregated with disease in the 2 families, suggesting that the families were not related or that the mutation was very old. In a family with autosomal dominant retinitis pigmentosa reported by {6:Iannaccone et al. (1996)} to be linked to 8q, {5:Guillonneau et al. (1999)} identified the R677X mutation in the RP1 gene. mutations RP1, ARG677TER number 1 clinvarAccessions RCV000081368;;1;;;RCV000006329;;1 status live name RETINITIS PIGMENTOSA 1 text Among 232 patients with autosomal dominant RP ({180100}) who did not have the R677X mutation ({603937.0001}), {11:Pierce et al. (1999)} found a deletion of 5 bp involving codons glu762 and asn763, causing a frameshift that introduced 16 novel amino acids before a premature termination codon. They referred to this mutation as leu762(5-bp del). mutations RP1, 5-BP DEL number 2 clinvarAccessions RCV000006330;;1 status live name RETINITIS PIGMENTOSA 1 text {11:Pierce et al. (1999)} found a patient with autosomal dominant RP ({180100}) who carried a heterozygous deletion of 4 bp involving codons asn763-thr764, resulting in a frameshift and premature termination 10 codons downstream. {11:Pierce et al. (1999)} referred to this mutation as asn763(4-bp del). mutations RP1, 4-BP DEL number 3 clinvarAccessions RCV000006331;;1 status live name RETINITIS PIGMENTOSA 1 dbSnps rs104894083 text In a British family (UK-RP1) with autosomal dominant retinitis pigmentosa ({180100}), previously studied by {7:Inglehearn et al. (1999)}, {13:Sullivan et al. (1999)} found that affected individuals carried a nonsense mutation in codon 679: CAA (gln) to TAA (stop). mutations RP1, GLN679TER number 4 clinvarAccessions RCV000006332;;1 status live name RECLASSIFIED - RP1 GENE POLYMORPHISM dbSnps rs2293869 text This variant, formerly titled HYPERTRIGLYCERIDEMIA, SUSCEPTIBILITY TO, has been reclassified because its relationship to that phenotype has not been confirmed. In a study of 55 unrelated nonsyndromic RP patients and 190 controls, all of Chinese origin, {15:Zhang et al. (2010)} determined that the N985Y variant ({dbSNP rs2293869}) was found at a high frequency among control subjects (27/190), and was not considered to be disease-causing. As of April 2014, the asn985-to-tyr (N985Y, c.2953A-T) variant had an overall population frequency of 35% ({3:Exome Variant Server, 2014}). {4:Fujita et al. (2003)} found an association between homozygosity for the tyr985 allele of the asn985-to-tyr (N985Y) polymorphism of the RP1 gene and susceptibility to hypertriglyceridemia ({145750}). The authors noted the necessity of confirmation and functional studies of this surprising finding. mutations RP1, ASN985TYR ({dbSNP rs2293869}) number 5 clinvarAccessions RCV000006333;;1;;;RCV000081369;;1 status live name RETINITIS PIGMENTOSA 1 dbSnps rs77775126 text In affected members of 2 consanguineous Pakistani families with retinitis pigmentosa ({180100}), {8:Khaliq et al. (2005)} identified homozygosity for a 1118C-T transition in exon 4 of the RP1 gene, resulting in a thr373-to-ile (T373I) substitution predicted to abolish the glycogen synthase (see {606784}) phosphorylation recognition site and to cause a conformational change in the protein. The parents and sibs of the patients who were heterozygous for the mutation had normal vision with no signs of RP on examination. mutations RP1, THR373ILE number 6 clinvarAccessions RCV000006334;;1 status live name RETINITIS PIGMENTOSA 1 text In affected members of a consanguineous Pakistani family with retinitis pigmentosa ({180100}), {8:Khaliq et al. (2005)} identified homozygosity for a 4-bp insertion at nucleotide 1461 in exon 4 of the RP1 gene, causing an immediate stop codon which results in a severely truncated protein of 487 rather than 2,156 amino acids. The parents and some unaffected sibs were heterozygous for the 4-bp insertion. mutations RP1, 4-BP INS, 1461TGAA number 7 clinvarAccessions RCV000006335;;1 prefix * titles alternativeTitles OXYGEN-REGULATED PHOTORECEPTOR PROTEIN 1; ORP1 preferredTitle RP1 GENE; RP1 textSectionList textSection textSectionTitle Cloning textSectionContent By its similarity to the homologous mouse gene, {11:Pierce et al. (1999)} identified a novel human photoreceptor-specific gene whose expression was modulated by retinal oxygen levels in vivo. The gene was initially designated ORP1 for 'oxygen-regulated protein-1' and was subsequently designated RP1 when it was found to be mutated in autosomal dominant RP (adRP). The predicted protein consists of 2,156 amino acids. The gene was first identified in mice in which differential display analysis using a mouse model of oxygen-induced retinal neovascularization identified genes that undergo significant changes in response to retinal hypoxia, and thus may be involved in the pathogenesis of retinal neovascularization. {5:Guillonneau et al. (1999)} studied a pool of photoreceptor-specific cDNAs isolated by subtractive hybridization of mRNAs from normal and photoreceptorless rd ({180072}) mouse retinas. One of the cDNAs mapped to proximal mouse chromosome 1 in a region homologous to human 8q11-q13, the locus of autosomal dominant RP1. Using the mouse cDNA as probe, they cloned the human RP1 cDNA and its corresponding gene and mapped it close to D8S509. textSectionName cloning textSectionTitle Gene Function textSectionContent {10:Liu et al. (2002)} investigated the location of the RP1 protein within human and mouse photoreceptor cells. They identified RP1 in connecting cilia and suggested that it might participate in transport of proteins between the inner and outer segments of photoreceptors or in maintenance of cilial structure. textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {11:Pierce et al. (1999)} found that the RP1 gene contains 4 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {11:Pierce et al. (1999)} mapped the ORP1 gene to chromosome 8q12-q13 by radiation hybrid analysis and FISH. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Retinitis Pigmentosa 1 In a patient from the extensive American family (UCLA-RP01) with retinitis pigmentosa (RP1; {180100}) studied by {1:Blanton et al. (1991)} and others, {11:Pierce et al. (1999)} identified a heterozygous nonsense mutation, arg677 to ter (R677X; {603937.0001}), in the ORP1 gene. Among 242 patients with adRP from unrelated families from the United States and Canada, 10 carried the R677X mutation; 2 deletion mutations ({603937.0002} and {603937.0003}) were found in 3 other individuals. These data suggested that approximately 4% of unrelated cases of adRP in the United States and Canada have pathogenic mutations in the ORP1 gene. {11:Pierce et al. (1999)} concluded that mutations in the ORP1 gene cause adRP and that the encoded protein has an important role in photoreceptor biology. {13:Sullivan et al. (1999)} likewise isolated the RP1 gene and identified mutations in the UCLA-RP01 family. They noted that the human RP1 region is partly syntenic with mouse chromosome 4, where a dominant retinal degeneration locus (Rd4) caused by a chromosomal inversion had been mapped ({12:Roderick et al., 1997}). In their search for RP1 candidate genes, they gave preference to ESTs that mapped to the RP1 region in the human and the Rd4 region in the mouse. This approach led them to a BAC clone that completely spanned the gene responsible for one of these ESTs. In addition to finding heterozygosity for the R677X mutation in the UCLA-RP01 family, they also found homozygosity for this mutation in the 2 severely affected members of the family. One had noticeable night blindness at age 6, visual field loss by 8, and severe retinal atrophy and nonrecordable ERGs by age 18. Her youngest brother, examined at age 7, had experienced night blindness since early childhood and already had severe visual field constriction. {13:Sullivan et al. (1999)} commented that the N terminus of the predicted protein encoded by the RP1 gene has similarity to that of the doublecortin protein, whose gene (DCX; {300121}) has been implicated in lissencephaly in humans. In a large family affected with adRP linked to the RP1 locus ({6:Iannaccone et al., 1996}), {5:Guillonneau et al. (1999)} identified the R677X mutation in all affected members. The mutation was absent in unaffected members and in 100 unrelated controls. The mutation was predicted to lead to rapid degradation of the mRNA or to the synthesis of a truncated protein lacking approximately 70% of its original length. To determine the frequency and range of mutations in RP1, {2:Bowne et al. (1999)} screened probands from 56 large adRP families for mutations in the entire gene. After preliminary results indicated that mutations seemed to cluster in a 442-nucleotide segment of exon 4, an additional 194 probands with adRP and 409 probands with other degenerative retinal diseases were tested for mutations in this region alone. {2:Bowne et al. (1999)} identified 8 different disease-causing mutations, 6 of which were novel, in 17 of the 250 adRP probands tested. All of these mutations were either nonsense or frameshift mutations and led to severely truncated proteins. Based on this study, {2:Bowne et al. (1999)} estimated that mutations in RP1 cause at least 7% of adRP and that the 5-bp deletion ({603937.0002}) and the R677X mutation account for 59% of these mutations. In affected members of 2 consanguineous Pakistani families with RP, {8:Khaliq et al. (2005)} identified homozygosity for a missense mutation in the RP1 gene ({603937.0006}). In affected members of another consanguineous Pakistani family with RP, they identified homozygosity for a 4-bp insertion in RP1 ({603937.0007}). History In the course of serial investigations of population genetics for hyperlipoproteinemia (see {145750}) in a population in east-central Japan, {4:Fujita et al. (2003)} recognized a correlation between lipoprotein variations and polymorphism of the RP1 locus. They reported an association between a missense polymorphism of the coding region of the gene, asn985 to tyr (N985Y; {603937.0005}), and plasma triglyceride levels in 332 adult individuals. Those who lacked the asn985 allele had significantly higher plasma triglyceride levels than those who had at least 1 asn985 allele; mean = 175.8 mg/dl vs 123.3 mg/dl; p = 0.0006, Mann-Whitney test. Similarly, the former subjects had significantly lower HDL cholesterol levels than the latter. Of the 280 individuals without an asn985 allele, approximately half presented with hypertriglyceridemia, whereas only one-quarter were hypertriglyceridemic among 52 individuals with the asn985 allele (P = 0.04). The mechanism of the association was unclear. The marker may be in linkage disequilibrium with other functional variants in the same region or the RP1 gene product may have wider implications in the organism than had been realized. {4:Fujita et al. (2003)} suggested that confirmation in geographically distinct populations and other ethnic groups will be useful. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {9:Liu et al. (2005)} studied retinal development in Rp1 -/- mice and found that as early as postnatal day 7, these mice had already undergone significant molecular retinal changes in response to the Rp1 lesion. The molecular responses to the disruption of Rp1 changed dramatically during development and were distinct from responses to the disruption of the photoreceptor transcription factors Crx ({602225}), Pde6b ({180072}), and Nrl ({162080}). Using microarray analysis, {9:Liu et al. (2005)} found evidence that the JNK signaling cascades are specifically compromised in Rp1 -/- retinas and that Rp1 and JNK cascades play integral roles in photoreceptor development and maintenance. textSectionName animalModel geneMapExists true editHistory alopez : 05/01/2014 carol : 7/11/2012 terry : 7/9/2012 alopez : 2/11/2009 alopez : 2/11/2009 carol : 11/20/2007 wwang : 12/13/2006 carol : 11/13/2006 carol : 7/12/2005 wwang : 6/22/2005 wwang : 6/20/2005 alopez : 4/1/2005 alopez : 2/18/2004 alopez : 1/15/2004 terry : 1/15/2004 mgross : 7/9/2002 mgross : 7/9/2002 cwells : 5/8/2001 carol : 4/25/2001 terry : 4/24/2001 terry : 4/24/2001 carol : 3/28/2001 carol : 8/9/2000 mgross : 11/5/1999 terry : 10/25/1999 alopez : 6/28/1999 dateCreated Mon, 28 Jun 1999 03:00:00 EDT creationDate Victor A. McKusick : 6/28/1999 epochUpdated 1398927600 dateUpdated Thu, 01 May 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/0888-7543(91)90008-3 publisherName Elsevier Science title Linkage mapping of autosomal dominant retinitis pigmentosa (RP1) to the pericentric region of human chromosome 8. mimNumber 603937 referenceNumber 1 publisherAbbreviation ES pubmedID 1783394 source Genomics 11: 857-869, 1991. authors Blanton, S. H., Heckenlively, J. R., Cottingham, A. W., Friedman, J., Sadler, L. A., Wagner, M., Friedman, L. H., Daiger, S. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10484783 publisherName HighWire Press title Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. mimNumber 603937 referenceNumber 2 publisherAbbreviation HighWire pubmedID 10484783 source Hum. Molec. Genet. 8: 2121-2128, 1999. authors Bowne, S. J., Daiger, S. P., Hims, M. M., Sohocki, M. M., Malone, K. A., McKie, A. B., Heckenlively, J. R., Birch, D. G., Inglehearn, C. F., Bhattacharya, S. S., Bird, A., Sullivan, L. S. pubmedImages false publisherUrl http://highwire.stanford.edu source http://evs.gs.washington.edu/EVS/ , 4/2014. mimNumber 603937 authors Exome Variant Server title NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. referenceNumber 3 title Hypertriglyceridemia associated with amino acid variation asn985tyr of the RP1 gene. mimNumber 603937 referenceNumber 4 pubmedID 12764676 source J. Hum. Genet. 48: 305-308, 2003. authors Fujita, Y., Ezura, Y., Emi, M., Ono, S., Takada, D., Takahashi, K., Uemura, K., Iino, Y., Katayama, Y., Bujo, H., Saito, Y. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10401003 publisherName HighWire Press title A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. mimNumber 603937 referenceNumber 5 publisherAbbreviation HighWire pubmedID 10401003 source Hum. Molec. Genet. 8: 1541-1546, 1999. authors Guillonneau, X., Piriev, N. I., Danciger, M., Kozak, C. A., Cideciyan, A. V., Jacobson, S. G., Farber, D. B. pubmedImages false publisherUrl http://highwire.stanford.edu source Invest. Ophthal. Vis. Sci. 37: S345 only, 1996. mimNumber 603937 authors Iannaccone, A., Cideciyan, A. V., Sheffield, V. C., Stone, E. M., Jacobson, S. G. title Phenotype of chromosome 8q-linked autosomal dominant retinitis pigmentosa. (Abstract) referenceNumber 6 articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10465120 publisherName HighWire Press title A new family linked to the RP1 dominant retinitis pigmentosa locus on chromosome 8q. mimNumber 603937 referenceNumber 7 publisherAbbreviation HighWire pubmedID 10465120 source J. Med. Genet. 36: 646-648, 1999. authors Inglehearn, C. F., McHale, J. C., Keen, T. J., Skirton, H., Lunt, P. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15863674 publisherName HighWire Press title Novel association of RP1 gene mutations with autosomal recessive retinitis pigmentosa. mimNumber 603937 referenceNumber 8 publisherAbbreviation HighWire pubmedID 15863674 source J. Med. Genet. 42: 436-438, 2005. authors Khaliq, S., Abid, A., Ismail, M., Hameed, A., Mohyuddin, A., Lall, P., Aziz, A., Anwar, K., Mehdi, S. Q. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16126734 publisherName HighWire Press title Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations. mimNumber 603937 referenceNumber 9 publisherAbbreviation HighWire pubmedID 16126734 source Hum. Molec. Genet. 14: 2945-2958, 2005. authors Liu, J., Huang, Q., Higdon, J., Liu, W., Xie, T., Yamashita, T., Cheon, K., Cheng, C., Zuo, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.iovs.org/cgi/pmidlookup?view=long&pmid=11773008 publisherName HighWire Press title Identification and subcellular localization of the RP1 protein in human and mouse photoreceptors. mimNumber 603937 referenceNumber 10 publisherAbbreviation HighWire pubmedID 11773008 source Invest. Ophthal. Vis. Sci. 43: 22-32, 2002. authors Liu, Q., Zhou, J., Daiger, S. P., Farber, D. B., Heckenlively, J. R., Smith, J. E., Sullivan, L. S., Zuo, J., Milam, A. H., Pierce, E. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/10305 publisherName Nature Publishing Group title Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. mimNumber 603937 referenceNumber 11 publisherAbbreviation NPG pubmedID 10391211 source Nature Genet. 22: 248-254, 1999. authors Pierce, E. A., Quinn, T., Meehan, T., McGee, T. L., Berson, E. L., Dryja, T. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(97)94717-0 publisherName Elsevier Science title A new dominant retinal degeneration (Rd4) associated with a chromosomal inversion in the mouse. mimNumber 603937 referenceNumber 12 publisherAbbreviation ES pubmedID 9205110 source Genomics 42: 393-396, 1997. authors Roderick, T. H., Chang, B., Hawes, N. L., Heckenlively, J. R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/10314 publisherName Nature Publishing Group title Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. mimNumber 603937 referenceNumber 13 publisherAbbreviation NPG pubmedID 10391212 source Nature Genet. 22: 255-259, 1999. authors Sullivan, L. S., Heckenlively, J. R., Bowne, S. J., Zuo, J., Hide, W. A., Gal, A., Denton, M., Inglehearn, C. F., Blanton, S. H., Daiger, S. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://link.springer.de/link/service/journals/00439/bibs/6098006/60980741.htm publisherName Springer title Genetic mapping of RP1 on 8q11-q21 in an Australian family with autosomal dominant retinitis pigmentosa reduces the critical region to 4 cM between D8S601 and D8S285. mimNumber 603937 referenceNumber 14 publisherAbbreviation Springer pubmedID 8931712 source Hum. Genet. 98: 741-743, 1996. authors Xu, S. Y., Denton, M., Sullivan, L., Daiger, S. P., Gal, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.molvis.org/molvis/v16/a149/ publisherName Molecular Vision title Differential pattern of RP1 mutations in retinitis pigmentosa. mimNumber 603937 referenceNumber 15 publisherAbbreviation MolVis pubmedID 20664799 source Molec. Vis. 16: 1353-1360, 2010. authors Zhang, X., Chen, L. J., Law, J. P., Lai, T. Y. Y., Chiang, S. W. Y., Tam, P. O. S., Chu, K. Y., Wang, N., Zhang, M., Pang, C. P. pubmedImages true publisherUrl http://www.molvis.org/molvis/ externalLinks mgiIDs MGI:1341105 mgiHumanDisease false ncbiReferenceSequences 530388513,5454015 nbkIDs NBK1417;;Retinitis Pigmentosa Overview dermAtlas false hprdIDs 04896 swissProtIDs P56715 zfinIDs ZDB-GENE-070912-612 uniGenes Hs.732820 refSeqAccessionIDs NG_009840.1 gtr true cmgGene false ensemblIDs ENSG00000104237,ENST00000220676 umlsIDs C1419605 genbankNucleotideSequences 50346528,71517568,221046409,162318121,148150418,225000239,5678833,194385777,20377020,194379417,511809551,5678820,478414007,34916064,22002202,18425295,116272376,5524300,116272374,5326859,21758134,116272372,5524303,116272370 geneTests true approvedGeneSymbols RP1 geneIDs 6101 proteinSequences 50346529,5524304,194385778,5678835,221046410,162318122,194379418,193783676,119607155,6225804,5678821,5454016,116272377,225000240,116272375,5524302,116272373,5326860,116272371 nextGxDx true locusSpecificDBs http://www.retina-international.org/files/sci-news/rp1mut.htm;;Mutations of the RP1 Gene

entryList

entry status live allelicVariantExists true epochCreated 520066800 geneMap geneSymbols THRB, ERBA2, THR1, PRTH sequenceID 2554 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 190160 phenotypeInheritance Autosomal dominant phenotype Thyroid hormone resistance phenotypeMimNumber 188570 phenotypeMappingKey 3 mimNumber 190160 phenotypeInheritance Autosomal recessive phenotype Thyroid hormone resistance, autosomal recessive phenotypeMimNumber 274300 phenotypeMappingKey 3 mimNumber 190160 phenotypeInheritance Autosomal dominant phenotype Thyroid hormone resistance, selective pituitary phenotypeMimNumber 145650 chromosomeLocationStart 24158643 chromosomeSort 100 chromosomeSymbol 3 mimNumber 190160 geneInheritance None confidence C mappingMethod REa, A, RE, Fd geneName Thyroid hormone receptor, beta (avian erythroblastic leukemia viral (v-erb-a) oncogene homolog-2) mouseMgiID MGI:98743 mouseGeneSymbol Thrb computedCytoLocation 3p24.2 cytoLocation 3p24.3 transcript uc003ccy.4 chromosomeLocationEnd 24536771 chromosome 3 contributors Matthew B. Gross - updated : 3/29/2012 Patricia A. Hartz - updated : 3/9/2012 John A. Phillips, III - updated : 7/18/2007 John A. Phillips, III - updated : 7/6/2007 Marla J. F. O'Neill - updated : 11/30/2006 Patricia A. Hartz - updated : 3/24/2006 Marla J. F. O'Neill - updated : 2/3/2006 John A. Phillips, III - updated : 8/2/2002 John A. Phillips, III - updated : 7/29/2002 John A. Phillips, III - updated : 7/26/2002 John A. Phillips, III - updated : 7/11/2002 John A. Phillips, III - updated : 7/1/2002 George E. Tiller - updated : 5/30/2002 Victor A. McKusick - updated : 1/9/2002 John A. Phillips, III - updated : 9/27/2001 Victor A. McKusick - updated : 4/17/2001 John A. Phillips, III - updated : 3/2/2001 Victor A. McKusick - updated : 1/3/2001 Victor A. McKusick - updated : 1/2/2001 John A. Phillips, III - updated : 9/29/2000 John A. Phillips, III - updated : 10/6/1999 Victor A. McKusick - updated : 8/24/1999 John A. Phillips, III - updated : 4/15/1999 Victor A. McKusick - updated : 3/1/1999 John A. Phillips, III - updated : 5/29/1997 John A. Phillips, III - updated : 4/17/1997 Stylianos E. Antonarakis - updated : 7/16/1996 externalLinks mgiIDs MGI:98743 mgiHumanDisease false ncbiReferenceSequences 189491770,530373054,530373064,358001056,530373060,358001055,530373062,530373056,189491767,530373058 ordrDiseases 301;;Generalized resistance to thyroid hormone refSeqAccessionIDs NG_009159.1 dermAtlas false hprdIDs 07521 swissProtIDs P10828 zfinIDs ZDB-GENE-990415-268 uniGenes Hs.187861 gtr true cmgGene false ensemblIDs ENSG00000151090,ENST00000356447 umlsIDs C0242988 genbankNucleotideSequences 23270887,148167132,21758020,148167133,148167134,148167135,7114465,148167131,71518807,21553245,180252,20336791,511857057,511857063,511857060,511857066,22271485,21755108,437814,6990424,216409681,305696384,20330870,10905447,3203442,325495460,76827090,12242035,305696625,34529732,167773516,33637068,21756164,33637070,33637072,33637074,33637076,33637078,33637080,76827894,79223771,31206,304435151,300679424,28173123,21756475,31999001,304435152,52242918 geneTests true approvedGeneSymbols THRB geneIDs 7068 proteinSequences 578806527,325495461,578806524,76827091,33637069,119584749,167773517,119584750,33637071,119584751,119584752,33637073,119584753,119584754,33637075,193788447,33637077,530373065,33637079,33637081,530373061,530373063,530373057,180253,76827895,530373055,586092,31207,300679425,189491771,437815,189491769,216409682,358001057,40806162 nextGxDx false clinicalSynopsisExists false mimNumber 190160 allelicVariantList allelicVariant status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918686 text In a father and son with inherited generalized resistance to thyroid hormone ({188570}), {61:Sakurai et al. (1989)} found a single guanine-to-cytosine replacement in the codon for amino acid 340 resulting in a glycine-to-arginine substitution (GLY340ARG) in the hormone-binding domain of the THRB gene. In vitro translation products of this mutant gene did not bind triiodothyronine. The mutation was not found in the unaffected mother. {68:Takeda et al. (1991)} referred to this mutation as gly345 to arg. The new numbering system takes into account the presence of 5 additional amino acids at the amino terminus as deduced from the corrected nucleotide sequence ({60:Sakurai et al., 1990}). The mutation was in exon 7 and occurred in family Mf studied in Chicago. In accordance with a new nomenclature recommended by {9:Beck-Peccoz et al. (1994)}, this mutation is designated G345R (gly345 to arg) in exon 9. mutations THRB, GLY345ARG number 1 clinvarAccessions RCV000013362;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918687 text In a family ('kindred A' originally reported by {39:Magner et al., 1986}) with generalized thyroid hormone resistance ({188570}), {74:Usala et al. (1990)} sequenced a major portion of the T3-binding domain of the ERBA2 gene because in vivo studies had shown an abnormality in T3-binding affinity of nuclear receptors. They showed a base substitution, cytosine to adenine, at cDNA position 1643, altering the proline codon at position 448 to histidine (PRO448HIS). By allele-specific hybridization, this base substitution was demonstrated in only 1 allele of 7 affected members and in none of 10 unaffected members of the kindred. It was not found in 2 other kindreds (kindreds B and D) in which linkage to ERBA2 had been demonstrated and was not found in 92 randomly tested ERBA2 alleles. All 3 kindreds showed inappropriately normal or elevated TSH with high levels of thyroid hormones. In addition to pituitary resistance to thyroid hormones, the kindreds also showed varying patterns of target organ resistance to the action of thyroid hormones. Only kindred A had short stature. Affected members of one of the other kindreds showed marked cognitive deficits. A 'hyperactivity' syndrome was present in some affected members. {68:Takeda et al. (1991)} referred to this mutation as pro453 to his (P453H), based on the revised count of amino acid residues. The mutation occurred in exon 8 and was identified in family Mh studied at the National Institutes of Health. {68:Takeda et al. (1991)} failed to find either the pro453-to-his mutation or the gly345-to-arg mutation ({190160.0001}) in any of 19 unrelated families with GRTH. The mode of inheritance was dominant in 13 families, unknown in 5 families, and clearly recessive in 1 family in which only the offspring of consanguineous subjects were affected. This mutation occurred in exon 10, according to the new numbering system of {9:Beck-Peccoz et al. (1994)}. mutations THRB, PRO453HIS number 2 clinvarAccessions RCV000013364;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE text In affected members of the original family reported by {56:Refetoff et al. (1967)}, in which GRTH segregated as an autosomal recessive ({274300}), {68:Takeda et al. (1991)} identified deletion of the THRB gene. Heterozygous members of the family were clinically normal. {68:Takeda et al. (1991)} concluded that the presence of a single normal allele was sufficient for normal receptor function, and suggested that in the dominant mode of GRTH inheritance the presence of an abnormal thyroid hormone receptor interferes with the function of the normal receptor in a dominant-negative fashion. This mutation is designated EX4-10DEL in the nomenclature of {9:Beck-Peccoz et al. (1994)}. mutations THRB, EX4-10DEL number 3 clinvarAccessions RCV000013365;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918688 text In 10 affected members of a family known as 'kindred D,' in which generalized thyroid hormone resistance segregated as an autosomal dominant trait ({188570}), {72:Usala et al. (1991)} identified heterozygosity for a 1305G-C transversion in the THRB gene, resulting in gln335-to-his (GLN335HIS) substitution. The mutation was not found in 6 unaffected family members. This mutation is designated gln340-to-his (Q340H) according to the revised numbering system of {9:Beck-Peccoz et al. (1994)}. mutations THRB, GLN340HIS number 4 clinvarAccessions RCV000013363;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE dbSnps rs121918689,rs387906515 text {73:Usala et al. (1991)} reported a 3-bp deletion in the T(3)-binding domain of the beta-receptor in kindred S with GRTH. The proband was the product of a consanguineous union of 2 heterozygotes and was homozygous for the defect ({274300}). The deletion of nucleotides 1295-1297 (CAC) resulted in the deduced loss of amino acid residue threonine at codon 332 (THR332DEL). The heterozygotes displayed elevated free T(4) levels and inappropriately normal thyroid-stimulating hormone levels characteristic of other kindreds with GRTH. However, the homozygote had markedly elevated TSH and free T(4) levels, and displayed profound abnormalities in brain development and linear growth. The findings in this family demonstrated the effects in man of both the heterozygous and the homozygous expression of a dominant-negative mutation. The clinical features of the homozygote were described by {49:Ono et al. (1991)}. He was born of first-cousin parents, both of whom were heterozygotes for GRTH. His clinical status suggested tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth and skeletal maturation and developmental delay but showed tachycardia. There were laboratory signs of profound pituitary resistance to thyroid hormone. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation involved deletion of amino acid 337 (thr337) encoded by exon 9. mutations THRB, THR337DEL number 5 clinvarAccessions RCV000013366;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918690 text In a patient with a sporadic form of GRTH ({188570}), {50:Parrilla et al. (1991)} identified an ala312-to-thr mutation (ALA312THR) due to a GCT-to-ACT change at nucleotide 1234 in exon 9. {50:Parrilla et al. (1991)} used the nucleotide and codon numbering as originally described by {75:Weinberger et al. (1986)}. This mutation is designated ala317-to thr(A317T) according the revised numbering system of {9:Beck-Peccoz et al. (1994)}. In 2 unrelated families and an unrelated individual with GRTH ({188570}), {78:Weiss et al. (1993)} identified heterozygosity for the A317T mutation in the THRB gene. In a father and 2 of his children with goiter and raised thyroid hormone levels, {53:Pohlenz et al. (1995)} identified heterozygosity for the same mutation. They commented on the fact that 'significant articulation problems' were present in the patient studied by {50:Parrilla et al. (1991)}. {42:Mixson et al. (1992)} found that more language abnormalities were thought to occur in kindreds with mutations in exon 9 than in those with mutations in exon 10. However, no abnormalities in language development, articulation problems, or signs consistent with dyslexia were found in the 3 affected members of the kindred they studied. {53:Pohlenz et al. (1995)} noted that a total of 38 different mutations in the THRB gene causing generalized resistance to thyroid hormone had been identified. mutations THRB, ALA317THR number 6 clinvarAccessions RCV000013369;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs28999969 text {50:Parrilla et al. (1991)} found a gly327-to-arg mutation (GLY327ARG) due to a GGG-to-AGG change at nucleotide 1279 in exon 9. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated G332R (gly332 to arg). mutations THRB, GLY332ARG number 7 clinvarAccessions RCV000013370;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs28999970 text {50:Parrilla et al. (1991)} found a gly340-to-val (GLY340VAL) mutation due to a GGT-to-GTT change at nucleotide 1319 in exon 9. The same codon is involved in the gly340-to-arg mutation ({190160.0001}). In the new nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated G345V (gly345 to val). mutations THRB, GLY345VAL number 8 clinvarAccessions RCV000013372;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs28999971 text {50:Parrilla et al. (1991)} found a GGG-to-GAG change at nucleotide 1325 of exon 9 resulting in substitution of glutamic acid for glycine-342 (GLY342GLU). This mutation was found in 4 individuals in 2 generations of a family, including a father-son combination. In accordance with the new nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated G347E (gly347 to glu). mutations THRB, GLY347GLU number 9 clinvarAccessions RCV000013373;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918691 text {50:Parrilla et al. (1991)} found an AGT-to-GTG change at nucleotide 1609 of exon 10 resulting in substitution of valine for methionine-437 (MET437VAL). In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated M442V (met442 to val). mutations THRB, MET442VAL number 10 clinvarAccessions RCV000013374;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT text In 1 of 7 unrelated families with generalized thyroid hormone resistance, {50:Parrilla et al. (1991)} found a frameshift mutation caused by insertion of a C in codon 443 in exon 10, resulting in a stop codon at 458. The patient was a sporadic case, i.e., neither parent showed the allele. {34:Kaneshige et al. (2001)} referred to this mutation as the PV mutation, presumably derived from the name of the patient. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was referred to as (C1627i)fr.sh.448(stop463) in exon 10. mutations THRB, 1-BP INS, 1627C number 11 clinvarAccessions RCV000013376;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs28933408 text In 6 members of 3 generations of a family, {50:Parrilla et al. (1991)} found heterozygosity for a pro448-to-thr mutation (PRO448THR) due to a CCT-to-ACT change involving nucleotide 1642 in exon 10. In a family in which the father and a son and daughter had generalized resistance to thyroid hormone, {66:Shuto et al. (1992)} found a cytosine-to-adenine transversion at nucleotide 1642 resulting in substitution of threonine (ACT) for proline (CCT) at codon 448. {74:Usala et al. (1990)} described a cytosine-to-adenine transversion at nucleotide position 1643 in a family with generalized thyroid hormone resistance ({190160.0002}). The phenotype was autosomal dominant in both families with mutations in codon 448; however, it differed in that hyperactivity syndrome, learning disability, and short stature were stressed as features of the phenotype in the family of {74:Usala et al. (1990)}. Studies of the 10 affected members demonstrated that they all had at least 3 of the following tissues resistant to thyroid hormone: pituitary, bone, liver, brain, and heart. In contrast, none of the affected members in the kindred of {66:Shuto et al. (1992)} showed short stature, bradycardia, elevated serum cholesterol, hyperactivity syndrome, or learning disability. The family was called to attention by a soft, symmetrically enlarged thyroid gland in the 11-year-old son. All 3 members had high levels of thyroid hormones with inappropriate secretion of TSH, and the father and sister also had small diffuse goiters with no stigmata of thyrotoxicosis. According to the new nomenclature by {9:Beck-Peccoz et al. (1994)}, {78:Weiss et al. (1993)} designated this mutation as P453T (pro453 to thr) in exon 10. The mutation was found in 2 separate families and consisted of a C-to-A transversion at nucleotide 1642. mutations THRB, PRO453THR number 12 clinvarAccessions RCV000013377;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918692 text In a Korean-Japanese kindred, {64:Sasaki et al. (1992)} found an A-to-G mutation at nucleotide 1612 resulting in substitution of glutamic acid for lysine-438 (LYS438GLU). The mutation was present in heterozygous state in each of the affected members of the family. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated K443E (lys443 to glu) in exon 8. mutations THRB, LYS443GLU number 13 clinvarAccessions RCV000013378;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918686 text In a family with thyroid hormone resistance reported by {14:Cooper et al. (1982)}, {3:Adams et al. (1992)} identified heterozygosity for a glycine-to-serine mutation at codon 340 (GLY340SER) in the hormone-binding domain of the receptor gene. In the new nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated G345S in exon 7. mutations THRB, GLY345SER number 14 clinvarAccessions RCV000013379;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918693 text {15:Cugini et al. (1992)} described autosomal dominant GRTH due to a guanine-to-adenine transition at nucleotide 1244, resulting in a change of arginine-315 to histidine (ARG315HIS). Affected members of this kindred appeared to have a relatively mild degree of resistance, with mean total thyroxine of only 192 +/- 24 nmol/L and inappropriately normal TSH levels. The oldest affected member studied was 62. The mutation was located further upstream than most previously described mutations; only ala312 to thr was further upstream. {78:Weiss et al. (1993)} found this mutation (designated arg320 to his in the new nomenclature) in 2 separate families with generalized thyroid hormone resistance. The distinctness of the mutant allele in the 2 families was supported by the fact that each was associated with a different CA repeat polymorphism. The change was a G-to-A transition at nucleotide 1244 in exon 9. mutations THRB, ARG320HIS number 15 clinvarAccessions RCV000013380;;1 status moved number 16 name MOVED TO {190160.0002} movedTo 190160.0002 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918694 text {10:Behr and Loos (1992)} demonstrated an ala229-to-thr (ALA229THR) mutation in heterozygous state in a mother, son, and daughter with generalized thyroid resistance. The 3 had some features of mild hyperthyroidism: slightly elevated resting pulse, experienced periodic tachycardia, weight loss, nervousness, and sweating were also observed, cold intolerance, and moderate goiter. All previously described mutations in THRB leading to GRTH had involved the T3-binding domain of the gene; this mutation was identified in the carboxy-terminal part of the hinge domain. It represented a GCC-to-ACC transition. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated A234T (ala234 to thr) in exon 5. mutations THRB, ALA234THR number 17 clinvarAccessions RCV000013381;;1 status live name THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY dbSnps rs121918695 text {25:Geffner et al. (1993)} described a patient with a severe form of selective pituitary resistance to thyroid hormones (PRTH; {145650}). The patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism at the age of 12 years ({21:Dulgeroff et al., 1992}). Bone age was advanced. Serum cholesterol was below the normal range and serum sex hormone binding globulin was 146% above the mean of the other female members of the kindred, consistent with hepatic hyperthyroidism. The father was unaffected. However, in both the proposita and her father, a G-to-A transition at nucleotide 1232 was found in 1 allele of the THRB gene, altering codon 311 from arginine to histidine (ARG311HIS). A half sister of the proposita also harbored the mutant allele and, like the father, was clinically normal. The receptor protein in the patient, synthesized with reticulocyte lysate, had significantly defective T3-binding activity. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wildtype and mutant alleles in both the patient and her unaffected father. Finally, the mutant receptor had no detectable dominant-negative activity in a transfection assay. Thus, in contrast to the many other THRB mutants responsible for the generalized form of thyroid hormone resistance, the receptor in this case appeared unable to antagonize normal receptor function. The arg311-to-his mutation may contribute to PRTH in this patient by inactivating 1 of the 2 THRB alleles but it cannot be the sole cause of the disease. {25:Geffner et al. (1993)} speculated about the possible reason for the disorder in the patient, e.g., the presence of a second mutation. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated R316H (arg316 to his) in exon 9. mutations THRB, ARG316HIS number 18 clinvarAccessions RCV000013382;;1 status live name THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY text {25:Geffner et al. (1993)} stated that they had found a leu325-to-phe mutation of the THRB gene in a previously published ({21:Dulgeroff et al., 1992}) patient with PRTH ({145650}). mutations THRB, LEU325PHE number 19 clinvarAccessions RCV000013383;;1 status moved number 20 name MOVED TO {190160.0006} movedTo 190160.0006 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918696 text {78:Weiss et al. (1993)} found heterozygosity for a 1243C-T transition in exon 9 of the THRB gene, resulting in an arg320-to-cys substitution in 2 separate families with generalized resistance to thyroid hormone ({188570}). Both families were of European ancestry, living in the United States, but were not known to be related. mutations THRB, ARG320CYS number 21 clinvarAccessions RCV000013384;;1 status moved number 22 name MOVED TO {190160.0015} movedTo 190160.0015 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918697 text {78:Weiss et al. (1993)} identified a 1297C-T transition in exon 9 of the THRB gene in 3 separate families with generalized thyroid hormone resistance ({188570}). The separateness of the mutations was indicated by the fact that in 1 family it was de novo and in the other 2 families it was associated with different CA repeat polymorphisms. This recurrent mutation occurred, like other recurrent ones, in a region of high CG content. The arg338-to-trp (R338W) mutation was associated with selective pituitary resistance to thyroid hormone ({145650}) in 4 of 5 kindreds studied by {2:Adams et al. (1994)}, as well as in 2 other reported cases ({43:Mixson et al., 1993}; {63:Sasaki et al., 1993}). The patient studied by {43:Mixson et al. (1993)} was the original patient (L-F3) reported as having PRTH by {26:Gershengorn and Weintraub (1975)}. {40:Mamanasiri et al. (2006)} studied a Turkish family in which 2 sibs had thyroid function tests (TFTs) characteristic of RTH, short stature, and psychiatric symptoms; their father had similar TFTs but no growth or psychiatric disturbances, and the mother had a normal phenotype and TFTs. Both sibs were found to be heterozygous for the R338W mutation, which was inherited from the father. The father was mosaic for the mutation, which was present in some lineages of somatic cells but not in skin fibroblasts. mutations THRB, ARG338TRP number 23 alternativeNames THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY, INCLUDED clinvarAccessions RCV000013386;;1;;;RCV000013385;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918698 text {12:Boothroyd et al. (1991)} identified heterozygosity for an arg438-to-his (R438H) mutation in a family with generalized thyroid hormone resistance ({188570}). The same mutation was found by {78:Weiss et al. (1993)} in 3 separate families. The separate origin of the mutation in these families was indicated by the fact that in one it was a de novo mutation and in the other 2 it was associated with different polymorphisms elsewhere in the gene. The mutation consisted of a G-to-A transition at nucleotide 1598. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated R438H in exon 10. mutations THRB, ARG438HIS number 24 clinvarAccessions RCV000013387;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED dbSnps rs121918699 text In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated M310T in exon 7. mutations THRB, MET310THR number 26 clinvarAccessions RCV000013367;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED dbSnps rs121918700 text This mutation was described as ASP317HIS by {42:Mixson et al. (1992)}. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated D322H in exon 9. mutations THRB, ASP322HIS number 27 clinvarAccessions RCV000013368;;1 status moved number 28 name MOVED TO {190160.0004} movedTo 190160.0004 status live name THYROID HORMONE RESISTANCE, GENERALIZED dbSnps rs28999970 text This mutation was described as GLY340ASP by {69:Takeda et al. (1992)}. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated G345D in exon 7. mutations THRB, GLY345ASP number 29 clinvarAccessions RCV000013371;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED dbSnps rs121918701 text This mutation was described as LEU445HIS by {42:Mixson et al. (1992)}. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated L450H in exon 10. mutations THRB, LEU450HIS number 30 clinvarAccessions RCV000013375;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED text This mutation was described by {69:Takeda et al. (1992)}. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was referred to as (C1644i)fr.sh.454(stop463) in exon 10. mutations THRB, 1-BP INS, 1644C number 31 clinvarAccessions RCV000013388;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED dbSnps rs121918702 text This mutation was described as PHE454CYS by {42:Mixson et al. (1992)}. In the nomenclature of {9:Beck-Peccoz et al. (1994)}, this mutation was designated F459C in exon 10. mutations THRB, PHE459CYS number 32 clinvarAccessions RCV000013389;;1 status live name THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY dbSnps rs121918693 text In a patient with a marked preponderance of thyrotoxic signs and symptoms associated with evidence of selective resistance to thyroid hormone (PRTH; {145650}), {2:Adams et al. (1994)} found a G-to-T transversion at nucleotide 1244 converting CGC (arg) to CTC (leu). The change occurred in exon 9. In the same study, the arg320-to-leu mutation was also found in a family with generalized resistance to thyroid hormone, which they concluded is fundamentally the same disorder. In the family in which the proband had PRTH, other relatives harboring the same receptor defect remained asymptomatic and clinically euthyroid despite comparably elevated thyroid hormone levels. Of 9 cases of PRTH studied by {2:Adams et al. (1994)}, 6 were associated with exon 9 mutations and 3 with exon 10 mutations. mutations THRB, ARG320LEU number 33 clinvarAccessions RCV000013390;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918703 text {76:Weiss et al. (1994)} studied 21 members of a family, of whom 12 exhibited the resistance to thyroid hormone phenotype ({188570}). They demonstrated heterozygosity for a T-to-C transition in the THRB gene that resulted in the replacement of cysteine-446 with an arginine. This mutation was present in the T3-binding domain and abolished T3 binding and hormone-mediated transactivation. The clinical characteristics in this family included goiter, tachycardia, and learning disabilities. mutations THRB, CYS446ARG number 34 clinvarAccessions RCV000013391;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE dbSnps rs121918704 text In a patient with generalized thyroid hormone resistance ({274300}), {77:Weiss et al. (1996)} identified homozygosity for a 1658T-C transition in the TRHB gene, resulting in the replacement of the normal val (GTG) with an ala (GCG) at codon 458. The proposita was 52 years old when she came to medical attention because of atrial fibrillation. There were no other stigmata of thyrotoxicosis or goiter despite serum T4 and free T4 levels that were elevated. The daughter had undergone subtotal thyroidectomy at 8 years of age, and at ages 16 and 19 years had been treated with radioiodine. They were of Irish and Scottish origin. The mutation was found in heterozygous state in both the mother and the father. mutations THRB, VAL458ALA number 35 clinvarAccessions RCV000013392;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918705 text {11:Behr et al. (1997)} described the analysis of a THRB gene in a patient with resistance to thyroid hormone ({188570}). The patient had both hypothyroid (severe mental retardation, hypoactivity, obesity) and hyperthyroid (tachycardia, low serum cholesterol) symptoms, as well as relatively early puberty, advanced bone age, and short stature. The patient was heterozygous, with a point mutation producing a premature stop-codon in exon 10, resulting in a 28-amino acid carboxy-terminal deletion of the THRB protein. mutations THRB, CYS434TER number 36 clinvarAccessions RCV000013393;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918706 text In a Japanese mother and son with resistance to thyroid hormone ({188570}), {48:Onigata et al. (1995)} identified heterozygosity for a G-to-A transition at codon 243 in exon 7 of the THRB gene. {80:Yagi et al. (1997)} studied the arg243-to-gln and arg243-to-trp ({190160.0038}) mutations, located in the hinge domain of THRB, and found that they do not significantly alter the binding affinity for T3, measured in vitro. These results suggested to {80:Yagi et al. (1997)} that the substitution of arg243 in thyroid hormone resistance acts by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T3 only after it binds to DNA. mutations THRB, ARG243GLN number 37 clinvarAccessions RCV000013394;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918707 text In 6-year-old female twins with generalized thyroid hormone resistance ({188570}), {52:Pohlenz et al. (1996)} identified heterozygosity for a 1012C-T transition in exon 7 of the THRB gene, resulting in an arg243-to-trp (R243W) substitution. The affected mother and maternal grandfather were also heterozygous for the mutation. See also {190160.0037}. mutations THRB, ARG243TRP number 38 clinvarAccessions RCV000013395;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT dbSnps rs121918708 text {13:Clifton-Bligh et al. (1998)} reported an 11-year-old female with generalized thyroid hormone resistance ({188570}) who presented with goiter and elevated serum free thyroxine (T4) and total triiodothyroxine (T3), with detectable thyroid-stimulating hormone (TSH; see {188540}) that responded normally to the administration of thyrotropin-releasing hormone (TRH). Abnormal thyroid function tests were also noted in her father and grandfather. PCR and direct sequencing of exon 10 of the THRB gene showed that all 3 individuals were heterozygous for a G-to-A transition (CGC to CAC) at nucleotide 1433, resulting in an arg383-to-his (R383H) substitution. While this mutation is located in a region not known to harbor naturally occurring mutations, it should be noted that it occurs at a CpG dinucleotide. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wildtype, negative transcriptional regulation of human TSH and TRH promoters was impaired in either THRB1 or THRB2 contexts, and wildtype receptor function was dominantly inhibited. {59:Safer et al. (1999)} reported an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received 3 escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell 25%, 36%, and 36%, respectively. Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal THR exons were sequenced, revealing the mutation R383H in a region not otherwise known to harbor THRB mutations. The authors stated that their clinical evaluation represented the most thorough documentation of the central thyroid hormone resistance phenotype in an individual with an identified THRB mutation. mutations THRB, ARG383HIS number 39 clinvarAccessions RCV000013396;;1 status live name THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY dbSnps rs121918709 text In a 29-year-old woman with pituitary thyroid hormone resistance ({145650}), {7:Asteria et al. (1999)} identified a 1296G-A transition in exon 9 of the THRB gene that resulted in a thr337-to-ala substitution. Her daughter was found to be heterozygous for the same mutation through chorionic villus sampling. mutations THRB, THR337ALA number 40 clinvarAccessions RCV000013397;;1 status live name THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT text {51:Phillips et al. (2001)} reported a child with extreme thyroid hormone resistance ({188570}) and a severe phenotype. The 22-month-old female presented with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain MRI showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). Molecular analyses of the patient's DNA identified a single-base deletion in her TR-beta gene, a C in codon 438 in exon 10, that resulted in a frameshift and premature termination at codon 442. Thus, the truncated receptor lacked the last 20 amino acids, including part of the hormone-binding domain. Cotransfection studies showed that the mutant thyroid receptor was transcriptionally inactive even in the presence of 10(-6)M T3 and had strong dominant-negative activity over the wildtype receptor. mutations THRB, 1-BP DEL, CODON 438, C number 41 clinvarAccessions RCV000013398;;1 status live name THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY text {79:Wu et al. (2006)} reported a newborn Turkish male, the child of nonconsanguineous parents, with severe but predominantly pituitary thyroid hormone resistance ({145650}) who presented at 6 days of age with respiratory distress, tachycardia, diaphoresis, and a thyroid gland 4 times normal size. The authors hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors. Sequencing of the THRB gene demonstrated a de novo heterozygous mutation, 1590_1591insT, resulting in a frameshift producing a mutant THR-beta with a 28-amino acid nonsense sequence and 2-amino acid carboxyl-terminal extension. The mutant TR-beta had impaired ability to recruit nuclear receptor corepressor (NCOR1; {600849}) but intact association with silencing mediator of retinoid and thyroid receptor (SMRT; {600848}). {79:Wu et al. (2006)} concluded that alterations in codons 436-453 in helix 11 of THR-beta result in significantly diminished association with NCOR but not with SMRT. mutations THRB, 1-BP INS, 1590T number 42 clinvarAccessions RCV000013399;;1 prefix * titles alternativeTitles V-ERB-A AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG 2; ERBA2;; ONCOGENE ERBA2;; ERBA-BETA preferredTitle THYROID HORMONE RECEPTOR, BETA; THRB textSectionList textSection textSectionTitle Description textSectionContent Thyroid hormone receptors (TRs) are nuclear receptors that mediate gene regulation by thyroid hormone (TH, or T3). TRs form monomers, homodimers, or heterodimers with retinoid X receptors (RXRs; see {180245}) at target DNA binding sites called TH-responsive elements (TREs). Two different genes, THRA ({190120}) and THRB, encode TRs, and both genes produce multiple TR isoforms through alternative splicing (summary by {45:Nagaya et al., 1996}). textSectionName description textSectionTitle Cloning textSectionContent {32:Jansson et al. (1983)} cloned the human ERBA2 gene. {75:Weinberger et al. (1986}) reported that the deduced THRB protein contains 450 amino acids. However, subsequent sequencing of the THRB cDNA and genomic clones predicted a 461-amino acid protein ({60:Sakurai et al., 1990}) {22:Evans (1988)} reviewed the molecular biology and physiology of the thyroid hormone receptor superfamily. textSectionName cloning textSectionTitle Nomenclature textSectionContent {38:Lazar and Chin (1990)} reviewed nuclear thyroid hormone receptors and noted the possible confusion of nomenclature. They stated that the so-called placental thyroid hormone receptor encoded by human chromosome 3 is the prototype beta form; its gene is referred to as ERBA2 or THRB. Isoform beta-1 is found in liver, heart, and brain; isoform beta-2 is specific for pituitary in the mouse and rat. The thyroid hormone alpha-1 receptor (ERBA1 or THRA, {190120}) is encoded by a gene on human chromosome 17. Alternative splicing of the gene transcript yields a species called alpha-2 or variant I, which is identical to alpha-1 for 370 amino acids, including the DNA-binding domain, but then diverges completely. The mRNA for this form is particularly abundant in the brain. textSectionName nomenclature textSectionTitle Mapping textSectionContent {70:Thompson et al. (1987)} presented evidence for the existence of at least 2 human thyroid hormone receptors. They noted that the receptor that is expressed in the mammalian central nervous system and in most other tissues except liver is encoded by a gene on chromosome 17 (THRA; {190120}). The receptor that is present in liver and some other tissues is encoded by a gene on chromosome 3 (THRB). By Southern blot analysis of DNA from somatic cell hybrids and in situ hybridization using the same human genomic probe, {57:Rider et al. (1987)} concluded that ERBA2 is located in the region 3pter-p21, rather than on chromosome 17 as previously held. Malignant lymphomas and salivary gland tumors consistent with chromosomal changes in that region have been observed. {16:Dobrovic et al. (1987)} mapped ERBA2, the thyroid hormone receptor gene, to 3p25-p21 and showed that it was deleted in small cell lung carcinoma (SCLC; {182280}) in all 6 cases studied. The assignment was done by study of somatic cell hybrids containing various translocations involving human chromosome 3. {20:Drabkin et al. (1987)} mapped an ERBA gene to 3p22-p21.33 by study of somatic cell hybrids and in situ hybridization with a DNA probe. By both somatic cell hybridization and in situ hybridization, {19:Drabkin et al. (1988)} showed that the ERBA2 gene is located on 3p24.1-p22. {19:Drabkin et al. (1988)} found, furthermore, that the ERBA2 locus was deleted in some but not in all cases of SCLC. Thus, the putative suppressor gene involved in that neoplasm is probably located centromeric to ERBA2. By nonisotopic in situ hybridization to metaphase chromosomes, {4:Albertson et al. (1989)} mapped the THRB gene to 3p24.3. THRB and 95 other loci on 3p were used by {71:Tory et al. (1992)} in the construction of a genetic linkage map through studies of 59 CEPH families. textSectionName mapping textSectionTitle Evolution textSectionContent {36:Koh and Moore (1999)} noted that the THRA, NR1D1 ({602408}), and RARA ({180240}) genes are linked on chromosome 17q, and that the NR1D1 gene overlaps an exon of the THRA gene on the opposite strand. They found that THRB, NR1D2 ({602304}), and RARB ({180220}) are similarly linked and oriented on chromosome 3p. The ancestral genes were duplicated before the divergence of vertebrates, since at least the TRs and RARs are also duplicated in birds and amphibians. textSectionName evolution textSectionTitle Gene Function textSectionContent Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. {31:Iskaros et al. (2000)} investigated the ontogeny of TR isoforms and related splice variants in 9 first-trimester fetal brains by semiquantitative RT-PCR analysis. Expression of the TR-beta-1, TR-alpha-1, and TR-alpha-2 isoforms was detected from 8.1 weeks' gestation. An additional truncated species was detected with the TR-alpha-2 primer set, consistent with the TR-alpha-3 splice variant described in the rat. All TR-alpha-derived transcripts were coordinately expressed and increased approximately 8-fold between 8.1 and 13.9 weeks' gestation. A more complex ontogenic pattern was observed for TR-beta-1, suggestive of a nadir between 8.4 and 12.0 weeks' gestation. The authors concluded that these findings point to an important role for the TR-alpha-1 isoform in mediating maternal thyroid hormone action during first-trimester fetal brain development. Most thyroid hormone receptor isoforms associate with coactivator proteins and mediate transcriptional activation only in the presence of thyroid hormone. The pituitary-specific THR-beta-2 isoform departs from this general rule and is able to interact with p160 coactivators, and to mediate transcriptional activation in both the absence and presence of hormone. {81:Yang and Privalsky (2001)} reported that this hormone-independent activation is mediated by contacts between the unique N terminus of THR-beta-2 and an internal interaction domain in the steroid receptor coactivator-1 (SRC1; {602691}) and glucocorticoid receptor-interacting protein-1 (GRIP1; {601993}) coactivators. These hormone-independent contacts between THR-beta-2 and the p160 coactivators are distinct in sequence and function from the LXXLL motifs that mediate hormone-dependent transcriptional activation and resemble instead a mode of coactivator recruitment previously observed only for the steroid hormone receptors and only in the presence of steroid hormone. The authors concluded that the transcriptional properties of the different thyroid hormone receptor isoforms represent a combinatorial mixture of repression, antirepression, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent In a kindred with autosomal dominant generalized thyroid hormone resistance (GRTH; {188570}), {8:Bale et al. (1988)} found that 1 allele of the ERBA-beta gene cosegregated with the resistance trait; maximum lod score = 3.91 at theta = 0.0. In this kindred a decrease in T3-binding affinity of salt-extracted fibroblast nuclear receptors had been demonstrated. In a father and son with generalized resistance to thyroid hormone, {61:Sakurai et al. (1989)} identified heterozygosity for a missense mutation in the THRB gene ({190160.0001}). In affected members of the original family reported by {56:Refetoff et al. (1967)}, in which GRTH segregated as an autosomal recessive trait ({274300}), {68:Takeda et al. (1991)} identified deletion of the THRB gene ({190160.0003}). {69:Takeda et al. (1992)} evaluated denaturing gradient gel electrophoresis (DGGE) in the rapid diagnosis of thyroid hormone resistance. In studies of affected members from 21 families, putative mutations were identified in 18 unrelated individuals. Sequencing confirmed the nature of the mutations in 9 of these individuals. All of the mutations were in the hormone-binding domain of the receptor; 13 of the 18 were in its center, exon 7. In 3 families, no mutations in the THRB gene were identified, suggesting the existence of mutations at other loci, possibly the THRA gene or other proteins involved in a thyroid hormone-dependent transactivation system. Of 22 families, the inheritance was recessive in 1, dominant in 15, and unknown in 6. {69:Takeda et al. (1992)} stated that they had studied 1 of the 7 families reported by {50:Parrilla et al. (1991)}, bringing the total of known families close to 30. {44:Nagaya et al. (1992)} presented experiments indicating that thyroid hormone receptor mutations that result in generalized growth hormone resistance compete with normal receptors at DNA binding sites in target genes to block normal receptor function; thus, the dominant-negative activity of such mutants may be explained by competition for receptor binding to DNA. However, {82:Yen et al. (1992)} presented observations of the gly340-to-arg mutation ({190160.0001}) in the MF family suggesting that the decreased sensitivity to T3 in the cells of the affected persons with this mutation is not due to abnormal interactions with the thyroid hormone receptor. Instead, the dominant-negative activity likely occurs by one or both of the following mechanisms: repression by mutant homodimers that bind to thyroid hormone response elements (TREs) in the presence of T3, and/or diminished ligand-regulated transcription by heterodimers of the mutant receptor or TRAP (thyroid hormone receptor auxiliary protein) heterodimers. In an analysis of 7 previously unreported families with GRTH, {50:Parrilla et al. (1991)} identified 6 single base substitutions and 1 single base insertion in the THRB gene. The 7 mutations were clustered in 2 regions of exons 9 and 10 in the ligand-binding domain of the receptor. Three of the families had a familial disorder; at least 3 of the others had a sporadic mutation as indicated by the fact that both parents were found to have 2 normal alleles. Thus, a 'dominant-negative' phenomenon is demonstrated. {78:Weiss et al. (1993)} indicated that 28 different point mutations in the THRB gene had been associated with GRTH. These mutations are clustered in 2 regions of the T3-binding domain of the gene at codons 310 to 347 and 417 to 453. {78:Weiss et al. (1993)} reported 6 examples of mutations occurring in apparently unrelated families; 3 of the mutations occurred in 3 different families each and the other 3 in 2 families each. In 11 of 15 families, the mutation was shown to be distinct either by the fact that de novo mutation was involved or that different polymorphisms were found in the gene. In other instances, ethnic difference, e.g., Japanese and Caucasian, supported distinctness. {78:Weiss et al. (1993)} pointed out that 28 of the 38 point mutations so far identified, including all those occurring in more than 1 family, are located in CG-rich areas of the THRB gene. Differences in clinical and laboratory findings in unrelated families harboring the same THRB mutations suggested that genetic variability of other factors modulate the expression of thyroid hormone action. {9:Beck-Peccoz et al. (1994)} presented a revised nomenclature for the THRB mutations causing resistance to thyroid hormone. They presented a tabulation of 27 mutations that had been published using the old notation; more recent publications already using the revised nomenclature were not included. The revision was necessitated by the advances in knowledge of the structure of the THRB gene. Cloning of the cDNA encoding THRB ({75:Weinberger et al., 1986}) initially had suggested an open reading frame of 450 amino acids. However, subsequent sequencing of this cDNA, as well as genomic clones, showed a guanine rather than adenine at nucleotide 288, generating a new initiation codon ({60:Sakurai et al., 1990}) and leading to a predicted protein sequence that contains 461 amino acids. In addition to differences in the numbering of the amino acids used in reported mutations, the exons had been numbered either from 00 to 8 or from 1 to 10, depending on the designation of noncoding exons. To avoid the confusion arising from a double nomenclature, {9:Beck-Peccoz et al. (1994)} recommended that the exons be numbered 1 through 10 with 1 and 2 corresponding to the previously designated 00 and 0, respectively, at the 5-prime end. A deduced sequence for THRB consisting of 461 amino acids and incorporating 5 additional residues (MTPNS) at the amino terminus was to be used. (Codons in the THRB gene are numbered according to the corrected coding sequence, which adds 5 amino acids to the amino terminus ({60:Sakurai et al., 1990}).) In the allelic variants listed below, 2 statements of the nature of the mutation are given when both have appeared in the literature. {30:Hayashi et al. (1994)} noted that the growing list of THRB mutations found in subjects with resistance to thyroid hormone led to the identification of 2 mutational 'hot' areas in the T3-binding domain of the protein. One of these 2 areas spans from codon 310 to 347 and the other from codon 438 to 459, the latter located 2 amino acids upstream of the carboxy terminus. The mutations occur with high frequency in CG-rich sequences. Not a single mutation had been identified in the region between the 2 'hot' areas. {23:Forman and Samuels (1990)} described this 'cold region,' which encodes 90 amino acids, contains 8 of the 9 heptad repeats, and appears to play an important role in receptor dimerization. {30:Hayashi et al. (1994)} produced 10 artificial mutant THRB genes in this 'cold' region according to the hotspot rule, i.e., C-to-T or G-to-A substitutions in CpGs. The properties of artificial mutants were compared with those of 6 naturally occurring mutants. Among all natural mutants, arg320 to his ({190160.0015}), manifesting a mild form of thyroid hormone resistance, showed the least impairment of T3-binding affinity. In contrast, T3-binding affinity was normal in 6 artificial mutants and reduced to a lesser extent than that of R320H in 3. One truncated mutant, R410X, did not bind T3. All natural mutants had impaired ability to transactivate T3-responsive elements and exhibited a strong dominant-negative effect on cotransfected wildtype receptor. Since the serum thyroid hormone levels required to compensate for the reduced binding affinity would be inferior to those found in subjects with R320H, natural mutations occurring in the cold region of the THRB gene should fail to manifest as thyroid hormone resistance or should escape detection. The artificial mutant R410X, resulting in a truncated protein, manifested thyroid hormone resistance only in the homozygous state. The cold region of the putative T3-binding domain is relatively insensitive to amino acid changes and, thus, may not be involved in a direct interaction with T3. {52:Pohlenz et al. (1996)} stated that 38 different point mutations had been documented in the THRB receptor as the cause of thyroid hormone resistance. Except for 2, all previously reported mutations were located in exons 9 or 10 in the hormone binding domain. In 45% of the mutations, a CpG dinucleotide was involved, indicating 2 hotspots at codons 310 to 347 and 438 to 459. {52:Pohlenz et al. (1996)} reported the second mutation in exon 7, R243W ({190160.0038}). {65:Seto and Weintraub (1996)} used PCR-coupled automated direct sequencing of genomic DNA for rapid molecular detection of mutations associated with GRTH to detect 2 novel mutations. In a 29-year-old woman with selective pituitary thyroid hormone resistance ({145650}), {7:Asteria et al. (1999)} identified a mutation in exon 9 of the THRB gene (T337A; {190160.0040}). She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3-prime-triiodothyroacetic acid (TRIAC) until the onset of pregnancy, when the therapy was discontinued to avoid possible adverse effects on fetal development. TRIAC therapy was reinstituted following recurrence of thyrotoxic features, and the fetus was shown also to be heterozygous for the T337A mutation. The authors advocated prenatal diagnosis of thyroid hormone resistance and adequate treatment of the disease in the case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy. {5:Ando et al. (2001)} performed RT-PCR to detect mutations in THRB from a surgically-resected TSH-secreting pituitary tumor (TSHoma). Analyses of the RT-PCR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of THRB2. This deletion was caused by alternative splicing of THRB2 mRNA, as near-consensus splice sequences were found at the junction site and no deletion or mutations were detected in the tumoral genomic DNA. This THRB variant lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSH-beta ({188540}) and glycoprotein hormone beta-subunit genes in cotransfection studies. Furthermore, the THRB variant showed dominant-negative activity against the wildtype THRB2. The authors concluded that aberrant alternative splicing of THRB2 mRNA generated an abnormal TR protein that accounted for the defective negative regulation of TSH in the TSHoma. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Thyroid hormone (triiodothyronine, T3) and its receptors are essential to the development of hearing. Congenital thyroid disorders impair hearing, and profound deafness is common in geographic areas where there is a prevalence of iodine deficiency. Also, hypothyroidism in mice and rats causes deformities in the organ of Corti and studies in these species indicate a critical window of development preceding the onset of hearing during which the hormone is required. To elucidate the role of thyroid hormone receptors alpha-1 (THRA; {190120}) and beta in the development of hearing, {58:Rusch et al. (1998)} investigated cochlear functions in mice lacking THRA1 or THRB. Both THRA1 and THRB are expressed during embryonic and postnatal development of the cochlea. Deletion of THRB by gene targeting in mice severely impairs the auditory-evoked brainstem response ({24:Forrest et al., 1996}). Also, human resistance to thyroid hormone is associated with THRB mutations, and some cases of resistance to thyroid hormone resulting from THRB mutations exhibit deafness or mild hearing impairment. Because THRB knockout mice do not display histologic defects in the cochlea ({24:Forrest et al., 1996}), {58:Rusch et al. (1998)} tested the hypothesis that THRB regulates functional rather than morphologic development of the cochlea. Their studies showed a defect in a potassium current in inner hair cells (IHCs). At the onset of hearing, IHCs in wildtype mice express a fast-activating potassium conductance, I(K,f), which transforms the immature IHC from a regenerative, spiking pacemaker to a high-frequency signal transmitter ({37:Kros et al., 1998}). {58:Rusch et al. (1998)} found that expression of I(K,f) was significantly retarded in THRB -/- mice, whereas the development of the endocochlear potential and other cochlear functions, including mechanoelectrical transduction in hair cells, progressed normally. THRA1 -/- mice expressed I(K,f) normally, in accord with their normal auditory-evoked brainstem response. Adult THRB -/- mice remained deaf with a permanently impaired auditory-evoked brainstem response, even when I(K,f) eventually approached normal magnitudes ({24:Forrest et al., 1996}). {58:Rusch et al. (1998)} suggested that this could be explained if early I(K,f) expression is required to facilitate the development of normal hearing in accord with the presence of a critical period for sensory inflow necessary for development of auditory function. This may be analogous to the visual system, in which studies of sensory deprivation have indicated a critical window for activity-dependent development of the ocular-dominance columns in the visual cortex ({35:Katz and Shatz, 1996}). These results implicated retarded expression of I(K,f) as a possible cause of hearing deficiency in the syndrome of resistance to thyroid hormone. Failure to activate this THRB-dependent function may also contribute to deafness in cases of congenital hypothyroidism. The studies of {58:Rusch et al. (1998)} suggested that it is unlikely that THRA1 mutations will be found to underlie deafness in human disorders. Whereas THRA1 and THRB1 are widely expressed, expression of the THRB2 splicing isoform is mainly limited to the pituitary, triiodothyronine-responsive thyrotropin-releasing hormone neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire Thrb locus exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the THRB2 splicing isoform to the function of the endocrine and auditory systems in vivo, {1:Abel et al. (1999)} generated mice with targeted disruption of the Thrb2 isoform. Thrb2-null mice had preserved expression of the Thra and Thrb1 isoforms. They developed a degree of central resistance to thyroid hormone similar to that in Thrb-null mice, indicating the important role of THRB2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone ({139250}) gene expression was marginally reduced. In contrast to Thrb-null mice, Thrb2-null mice exhibited no evidence of hearing impairment, indicating that THRB1 and THRB2 subserve divergent roles in the regulation of auditory function. To understand the molecular basis underlying the action of mutant THRB in vivo, {33:Kaneshige et al. (2000)} generated mice with a targeted mutation in the Thrb gene by using homologous recombination and the Cre/loxP system. The mutation in the THRB gene, referred to as PV, was the pro448-to-thr mutation ({190160.0012}). Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with generalized resistance to thyroid hormone. Homozygous PV mice exhibited severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype was distinct from that seen in mice with a null mutation of the Thrb gene. {6:Araki et al. (2005)} found that Thrb with the dominant-negative PV mutation bound as a homodimer or as a heterodimer with Pparg ({601487}) or retinoid X receptor (see RXRA; {180245}) to peroxisome proliferator response elements (PPREs), thereby inhibiting interaction of Pparg with Rxr on PPREs. Thrb with the PV mutation repressed ligand-dependent Pparg activation following expression in monkey kidney cells, and chromatin immunoprecipitation studies indicated that repression was due to recruitment of corepressors to the promoters of Pparg target genes in vivo. {83:Ying et al. (2006)} found elevated Pttg1 ({604147}) levels in the thyroid tumors of PV mutant mice. Pttg1 was physically associated with Thrb as well as mutant PV receptor; however, T3-induced Thrb-mediated proteasomal degradation of Pttg1 did not occur when Pttg1 was associated with mutant Thrb, and accumulated Pttg1 impeded mitotic progression in Thrb mutant-expressing cells. Proteasomal degradation was activated by direct interaction of liganded Thrb with Src3 (NCOA3; {601937}). {83:Ying et al. (2006)} concluded that PTTG1 is regulated by liganded THRB and that loss of this regulatory function in THRB mutants leads to an accumulation of PTTG1 that disrupts mitotic progression and thus may contribute to thyroid carcinogenesis. To evaluate the respective contributions of THRA and THRB in the regulation of CYP7A ({118455}), the rate-limiting enzyme in the synthesis of bile acids, {28:Gullberg et al. (2000)} studied the responses to 2% dietary cholesterol and T3 in THRA and THRB knockout mice under hypo- and hyperthyroid conditions. Their experiments showed that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in THRB -/-, but not in THRA-/-, mice, identifying THRB as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient THRB -/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent that wildtype controls did. The authors concluded that the latter results lend strong support to the concept that THRs may exert regulatory effects in vivo independent of T3. THRB2 is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. {46:Ng et al. (2001)} deleted the Thrb gene in mice, causing the selective loss of middle (M, 'green') cones and a concomitant increase in short (S, 'blue') opsin immunoreactive cones. Moreover, the gradient of cone distribution was disturbed, with S-cones becoming widespread across the retina. The results indicated that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and revealed an essential role for THRB2 in the commitment to an M-cone identity. The findings raised the possibility that mutations of the THRB gene may be associated with human cone disorders. Although thyroid hormones are thought to act principally by binding to their nuclear receptors, thyroid receptor knockout animals have normal CNS structure and function. To investigate this discrepancy further, {29:Hashimoto et al. (2001)} introduced a T3-binding mutation into the mouse Thrb gene by homologous recombination. Because of this T3-binding defect, the mutant thyroid hormone receptor constitutively interacted with corepressor proteins and mimicked the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrated the specific and deleterious action of unliganded thyroid hormone receptor in the brain and suggested the importance of corepressors bound to thyroid receptor in the pathogenesis of hypothyroidism. {47:Ng et al. (2001)} determined that a targeted mutation in the THRA gene suppresses deafness and thyroid hyperactivity in transgenic Thrb-null mice. The THRA splice variant TR-alpha-1 receptor is nonessential for hearing, and the shorter TR-alpha-2 splice variant has unknown function but neither binds thyroid hormone nor transactivates. The targeted mutation deletes TR-alpha-2 and concomitantly causes overexpression of TR-alpha-1 as a consequence of the exon structure of the gene. The Thra-null mice had normal auditory thresholds, suggesting that TR-alpha-2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the mutated allele was revealed upon its introduction into Thrb-null mice, where it suppressed the auditory and thyroid phenotypes caused by loss of THRB. The authors proposed a modifying function for a THRA allele and suggested that increased expression of TR-alpha-1 may substitute for the absence of THRB. {54:Puzianowska-Kuznicka et al. (2002)} tested the hypothesis that the functions of TRs could be impaired in cancer tissues by aberrant expression and/or somatic mutations. As a model system, they selected human thyroid papillary cancer. They found that the mean expression levels of THRB mRNA and THRA mRNA were significantly lower, whereas the protein levels of THRB1 and THRA1 were higher in cancer tissues than in healthy thyroid. Sequencing of THRB1 and THRA1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such THRB1 or THRA1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant-negative activity. The authors concluded that these findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma. textSectionName animalModel textSectionTitle History textSectionContent {41:Middleton et al. (1986)} identified a RFLP for the ERBA2 gene. By in situ hybridization, {27:Gosden et al. (1986)} mapped the ERBA2 gene as well as a related gene to chromosome 17q21.3. {18:Douglas et al. (1991)} discussed the confusion that surrounded the ERBA genes. By screening a genomic library with v-erbA, {32:Jansson et al. (1983)} isolated 2 types of clones. One clone, called erbA1, is now known to define the THRA locus on chromosome 17 ({190120}). The second clone, erbA2, seemed to map both to chromosome 17 and chromosome 3. In response to this inconsistent assignment, the genes for erbA2 and erbA-beta were given different designations (ERBA2 and ERBA1, respectively) by Human Gene Mapping 9. Using pulsed field gel electrophoresis, {18:Douglas et al. (1991)} reported that the ERBA2 and ERBA1 loci are both on chromosome 3 separated by 50 to 120 kb. They stated that the erbA-beta probe may recognize a separate but closely linked gene on chromosome 3. textSectionName history geneMapExists true editHistory mgross : 03/29/2012 mgross : 3/29/2012 terry : 3/9/2012 carol : 4/20/2009 carol : 11/28/2007 wwang : 7/30/2007 alopez : 7/18/2007 carol : 7/6/2007 carol : 7/6/2007 wwang : 11/30/2006 mgross : 3/28/2006 terry : 3/24/2006 carol : 2/21/2006 carol : 2/6/2006 carol : 2/6/2006 carol : 2/3/2006 joanna : 5/27/2005 terry : 3/23/2005 terry : 2/22/2005 terry : 6/2/2004 alopez : 3/17/2004 cwells : 8/2/2002 tkritzer : 7/29/2002 tkritzer : 7/26/2002 alopez : 7/11/2002 alopez : 7/1/2002 cwells : 5/30/2002 joanna : 5/16/2002 joanna : 5/16/2002 carol : 1/19/2002 terry : 1/9/2002 alopez : 10/30/2001 alopez : 9/27/2001 mcapotos : 5/8/2001 mcapotos : 4/25/2001 terry : 4/17/2001 mgross : 3/2/2001 mcapotos : 1/10/2001 terry : 1/3/2001 mgross : 1/2/2001 mgross : 10/3/2000 terry : 9/29/2000 carol : 4/18/2000 alopez : 10/6/1999 alopez : 10/6/1999 mgross : 9/2/1999 terry : 8/24/1999 mgross : 6/22/1999 carol : 6/12/1999 carol : 6/11/1999 terry : 6/9/1999 mgross : 4/15/1999 carol : 3/22/1999 terry : 3/1/1999 alopez : 11/13/1998 dkim : 9/11/1998 alopez : 5/15/1998 dholmes : 11/11/1997 dholmes : 11/11/1997 dholmes : 10/24/1997 terry : 7/8/1997 alopez : 6/26/1997 mark : 6/16/1997 jenny : 6/5/1997 jenny : 5/29/1997 jenny : 5/27/1997 jenny : 5/21/1997 jenny : 5/20/1997 jamie : 1/15/1997 jamie : 1/8/1997 terry : 1/6/1997 mark : 11/7/1996 terry : 10/31/1996 mark : 7/17/1996 mark : 7/16/1996 mark : 1/31/1996 terry : 1/25/1996 mark : 6/21/1995 mimadm : 6/7/1995 carol : 11/29/1994 terry : 11/23/1994 carol : 10/20/1993 carol : 7/13/1993 dateCreated Wed, 25 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/25/1986 epochUpdated 1333004400 dateUpdated Thu, 29 Mar 2012 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1172/JCI6397 publisherName Journal of Clinical Investigation title Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. mimNumber 190160 referenceNumber 1 publisherAbbreviation JCI pubmedID 10430610 source J. Clin. Invest. 104: 291-300, 1999. authors Abel, E. D., Boers, M.-E., Pazos-Moura, C., Moura, E., Kaulbach, H., Zakaria, M., Lowell, B., Radovick, S., Liberman, M. C., Wondisford, F. pubmedImages true publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI117362 publisherName Journal of Clinical Investigation title Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor beta gene. mimNumber 190160 referenceNumber 2 publisherAbbreviation JCI pubmedID 8040303 source J. Clin. Invest. 94: 506-515, 1994. authors Adams, M., Matthews, C., Collingwood, T. N., Tone, Y., Beck-Peccoz, P., Chatterjee, K. K. pubmedImages false publisherUrl http://www.jci.org title Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome. mimNumber 190160 referenceNumber 3 pubmedID 1563081 source Clin. Endocr. 36: 281-289, 1992. authors Adams, M., Nagaya, T., Tone, Y., Jameson, J. L., Chatterjee, V. K. K. pubmedImages false title Localization of polymorphic DNA probes frequently deleted in lung carcinoma. mimNumber 190160 referenceNumber 4 pubmedID 2550353 source Hum. Genet. 83: 127-132, 1989. authors Albertson, D. G., Sherrington, P. D., Rabbitts, P. H. pubmedImages false articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=11518802 publisherName HighWire Press title Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance. mimNumber 190160 referenceNumber 5 publisherAbbreviation HighWire pubmedID 11518802 source Molec. Endocr. 15: 1529-1538, 2001. authors Ando, S., Sarlis, N. J., Krishnan, J., Feng, X., Refetoff, S., Zhang, M. Q., Oldfield, E. H., Yen, P. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16260719 publisherName HighWire Press title Thyroid hormone receptor beta mutants: dominant negative regulators of peroxisome proliferator-activated receptor gamma action. mimNumber 190160 referenceNumber 6 publisherAbbreviation HighWire pubmedID 16260719 source Proc. Nat. Acad. Sci. 102: 16251-16256, 2005. authors Araki, O., Ying, H., Furuya, F., Zhu, X., Cheng, S. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=10022392 publisherName HighWire Press title Prenatal diagnosis of thyroid hormone resistance. mimNumber 190160 referenceNumber 7 publisherAbbreviation HighWire pubmedID 10022392 source J. Clin. Endocr. Metab. 84: 405-410, 1999. authors Asteria, C., Rajanayagam, O., Collingwood, T. N., Persani, L., Romoli, R., Mannavola, D., Zamperini, P., Buzi, F., Ciralli, F., Chatterjee, V. K. K., Beck-Peccoz, P. pubmedImages false publisherUrl http://highwire.stanford.edu source Am. J. Hum. Genet. 43: A77, 1988. mimNumber 190160 authors Bale, A. E., Usala, S. J., Gesundheit, N., Weinberger, C., Lash, R. W., Wondisford, F. E., McBride, O. W., Weintraub, B. D. title The gene for generalized thyroid hormone resistance (GTHR) is tightly linked to and may be identical with the proto-oncogene, c-erbA-beta. (Abstract) referenceNumber 8 title Nomenclature of thyroid hormone receptor-beta gene mutations in resistance to thyroid hormone: consensus statement from the First Workshop on Thyroid Hormone Resistance, 10-11 July 1993, Cambridge, UK. mimNumber 190160 referenceNumber 9 pubmedID 8013151 source Clin. Endocr. 40: 697-700, 1994. authors Beck-Peccoz, P., Chatterjee, V. K. K., Chin, W. W., DeGroot, L. J., Jameson, J. L., Nakamura, H., Refetoff, S., Usala, S. J., Weintraub, B. D. pubmedImages false articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=1324420 publisherName HighWire Press title A point mutation (ala229-to-thr) in the hinge domain of the c-erbA-beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance. mimNumber 190160 referenceNumber 10 publisherAbbreviation HighWire pubmedID 1324420 source Molec. Endocr. 6: 1119-1126, 1992. authors Behr, M., Loos, U. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9100577 publisherName HighWire Press title Deoxyribonucleic acid binding and transcriptional silencing by a truncated c-erbA-beta-1 thyroid hormone receptor identified in a severely retarded patient with resistance to thyroid hormone. mimNumber 190160 referenceNumber 11 publisherAbbreviation HighWire pubmedID 9100577 source J. Clin. Endocr. Metab. 82: 1081-1087, 1997. authors Behr, M., Ramsden, D. B., Loos, U. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(91)90151-V publisherName Elsevier Science title Single base mutation in the hormone binding domain of the thyroid hormone receptor beta gene in generalized thyroid hormone resistance demonstrated by single stranded conformation polymorphism analysis. mimNumber 190160 referenceNumber 12 publisherAbbreviation ES pubmedID 1677564 source Biochem. Biophys. Res. Commun. 178: 606-612, 1991. authors Boothroyd, C. V., Teh, B. T., Hayward, N. K., Hickman, P. E., Ward, G. J., Cameron, D. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=9605924 publisherName HighWire Press title A novel TR-beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation. mimNumber 190160 referenceNumber 13 publisherAbbreviation HighWire pubmedID 9605924 source Molec. Endocr. 12: 609-621, 1998. authors Clifton-Bligh, R. J., de Zegher, F., Wagner, R. L., Collingwood, T. N., Francois, I., Van Helvoirt, M., Fletterick, R. J., Chatterjee, V. K. K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0026-0495(82)90242-6 publisherName Elsevier Science title Familial thyroid hormone resistance. mimNumber 190160 referenceNumber 14 publisherAbbreviation ES pubmedID 7200565 source Metabolism 31: 504-509, 1982. authors Cooper, D. S., Ladenson, P. W., Nisula, B. C., Dunn, J. F., Chapman, E. M., Ridgway, E. C. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1314846 publisherName HighWire Press title An arginine to histidine mutation in codon 315 of the c-erbA-beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3-prime-triiodothyronine binding activity. mimNumber 190160 referenceNumber 15 publisherAbbreviation HighWire pubmedID 1314846 source J. Clin. Endocr. Metab. 74: 1164-1170, 1992. authors Cugini, C. D., Jr., Leidy, J. W., Jr., Chertow, B. S., Berard, J., Bradley, W. E. C., Menke, J. B., Hao, E.-H., Usala, S. J. pubmedImages false publisherUrl http://highwire.stanford.edu source Cytogenet. Cell Genet. 46: 607, 1987. mimNumber 190160 authors Dobrovic, A., Houle, B., Belouchi, A., Bradley, W. E. C. title The thyroid hormone receptor (THR) maps to the chromosome region 3p21-3p25 and is deleted in small cell lung carcinoma. (Abstract) referenceNumber 16 articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=2891438 publisherName HighWire Press title erbA-related sequence coding for DNA-binding hormone receptor localized to chromosome 3p21-3p25 and deleted in small cell lung carcinoma. mimNumber 190160 referenceNumber 17 publisherAbbreviation HighWire pubmedID 2891438 source Cancer Res. 48: 682-685, 1988. authors Dobrovic, A., Houle, B., Belouchi, A., Bradley, W. E. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0888-7543(91)90274-I publisherName Elsevier Science title A pulsed-field gel electrophoresis map locates the polymorphic probes for ERBA2 and erbA-beta within 120 kb of each other, confirming that THRB (formerly ERBA2) maps to chromosome 3. mimNumber 190160 referenceNumber 18 publisherAbbreviation ES pubmedID 1672299 source Genomics 9: 398-400, 1991. authors Douglas, J. B., Daly, M. C., Rabbitts, P. H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2848257 publisherName HighWire Press title Localization of human ERBA2 to the 3p22-3p24.1 region of chromosome 3 and variable deletion in small cell lung cancer. mimNumber 190160 referenceNumber 19 publisherAbbreviation HighWire pubmedID 2848257 source Proc. Nat. Acad. Sci. 85: 9258-9262, 1988. authors Drabkin, H., Kao, F.-T., Hartz, J., Hart, I., Gazdar, A., Weinberger, C., Evans, R., Gerber, M. pubmedImages false publisherUrl http://highwire.stanford.edu source Am. J. Hum. Genet. 41: A25, 1987. mimNumber 190160 authors Drabkin, H. A., Kao, F.-T., Weinberger, C., Evans, R. title Human c-erb-A is located at chromosome 3p21.33-p22. (Abstract) referenceNumber 20 articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1400873 publisherName HighWire Press title Bromocriptine and triac therapy for hyperthyroidism due to pituitary resistance to thyroid hormone. mimNumber 190160 referenceNumber 21 publisherAbbreviation HighWire pubmedID 1400873 source J. Clin. Endocr. Metab. 75: 1071-1075, 1992. authors Dulgeroff, A. J., Geffner, M. E., Koyal, S. N., Wong, M., Hershman, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=3283939 publisherName HighWire Press title The steroid and thyroid hormone receptor superfamily. mimNumber 190160 referenceNumber 22 publisherAbbreviation HighWire pubmedID 3283939 source Science 240: 889-895, 1988. authors Evans, R. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=2172797 publisherName HighWire Press title Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. mimNumber 190160 referenceNumber 23 publisherAbbreviation HighWire pubmedID 2172797 source Molec. Endocr. 4: 1293-1301, 1990. authors Forman, B. M., Samuels, H. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0796-354 publisherName Nature Publishing Group title Thyroid hormone receptor beta is essential for development of auditory function. mimNumber 190160 referenceNumber 24 publisherAbbreviation NPG pubmedID 8673137 source Nature Genet. 13: 354-357, 1996. authors Forrest, D., Erway, L. C., Ng, L., Altschuler, R., Curran, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1172/JCI116233 publisherName Journal of Clinical Investigation title An arginine to histidine mutation in codon 311 of the C-erbA-beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype. mimNumber 190160 referenceNumber 25 publisherAbbreviation JCI pubmedID 8381821 source J. Clin. Invest. 91: 538-546, 1993. authors Geffner, M. E., Su, F., Ross, N. S., Hershman, J. M., Van Dop, C., Menke, J. B., Hao, E., Stanzak, R. 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G., Rout, D., De Angelis, C. pubmedImages false articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=11075809 publisherName HighWire Press title Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7-alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. mimNumber 190160 referenceNumber 28 publisherAbbreviation HighWire pubmedID 11075809 source Molec. Endocr. 14: 1739-1749, 2000. authors Gullberg, H., Rudling, M., Forrest, D., Angelin, B., Vennstrom, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11274423 publisherName HighWire Press title An unliganded thyroid hormone receptor causes severe neurological dysfunction. mimNumber 190160 referenceNumber 29 publisherAbbreviation HighWire pubmedID 11274423 source Proc. Nat. Acad. Sci. 98: 3998-4003, 2001. authors Hashimoto, K., Curty, F. H., Borges, P. P., Lee, C. E., Abel, E. D., Elmquist, J. K., Cohen, R. N., Wondisford, F. E. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI117376 publisherName Journal of Clinical Investigation title Mutations of CpG dinucleotides located in the triiodothyronine (T3)-binding domain of the thyroid hormone receptor (TR)beta gene that appears to be devoid of natural mutations may not be detected because they are unlikely to produce the clinical phenotype of resistance to thyroid hormone. mimNumber 190160 referenceNumber 30 publisherAbbreviation JCI pubmedID 8040316 source J. Clin. 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Metab. 85: 2620-2623, 2000. authors Iskaros, J., Pickard, M., Evans, I., Sinha, A., Hardiman, P., Ekins, R. pubmedImages false publisherUrl http://highwire.stanford.edu title Isolation and characterization of multiple human genes homologous to the oncogenes of avian erythroblastosis virus. mimNumber 190160 referenceNumber 32 pubmedID 6313346 source EMBO J. 2: 561-565, 1983. authors Jansson, M., Philipson, L., Vennstrom, B. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11069286 publisherName HighWire Press title Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. mimNumber 190160 referenceNumber 33 publisherAbbreviation HighWire pubmedID 11069286 source Proc. Nat. Acad. Sci. 97: 13209-13214, 2000. authors Kaneshige, M., Kaneshige, K., Zhu, X., Dace, A., Garrett, L., Carter, T. A., Kazlauskaite, R., Pankratz, D. 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I. pubmedImages false articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1846005 publisherName HighWire Press title A new point mutation in the 3,5,3-prime-triiodothyronine-binding domain of the c-erbA-beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance. mimNumber 190160 referenceNumber 72 publisherAbbreviation HighWire pubmedID 1846005 source J. Clin. Endocr. Metab. 72: 32-38, 1991. authors Usala, S. J., Menke, J. B., Watson, T. L., Berard, J., Bradley, W. E. C., Bale, A. E., Lash, R. W., Weintraub, B. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=1653889 publisherName HighWire Press title A homozygous deletion in the c-erbA-beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. mimNumber 190160 referenceNumber 73 publisherAbbreviation HighWire pubmedID 1653889 source Molec. Endocr. 5: 327-335, 1991. authors Usala, S. J., Menke, J. B., Watson, T. L., Wondisford, F. E., Weintraub, B. D., Berard, J., Bradley, W. E. C., Ono, S., Mueller, O. T., Bercu, B. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI114438 publisherName Journal of Clinical Investigation title A base mutation of the C-erbA-beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance: molecular heterogeneity in two other kindreds. mimNumber 190160 referenceNumber 74 publisherAbbreviation JCI pubmedID 2153155 source J. Clin. Invest. 85: 93-100, 1990. authors Usala, S. J., Tennyson, G. E., Bale, A. E., Lash, R. W., Gesundheit, N., Wondisford, F. E., Accili, D., Hauser, P., Weintraub, B. D. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1038/324641a0 publisherName Nature Publishing Group title The c-erb-A gene encodes a thyroid hormone receptor. mimNumber 190160 referenceNumber 75 publisherAbbreviation NPG pubmedID 2879243 source Nature 324: 641-646, 1986. authors Weinberger, C., Thompson, C. C., Ong, E. S., Lebo, R., Gruol, D. J., Evans, R. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=8175986 publisherName HighWire Press title A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone. mimNumber 190160 referenceNumber 76 publisherAbbreviation HighWire pubmedID 8175986 source J. Clin. Endocr. Metab. 78: 1253-1256, 1994. authors Weiss, R. E., Chyna, B., Duell, P. B., Hayashi, Y., Sunthornthepvarakul, T., Refetoff, S. pubmedImages false publisherUrl http://highwire.stanford.edu title A new mutation in the thyroid hormone receptor (TR) beta gene (V458A) in a family with resistance to thyroid hormone (RTH). mimNumber 190160 referenceNumber 77 pubmedID 8875752 source Thyroid 6: 311-312, 1996. authors Weiss, R. E., Tunca, H., Gerstein, H. C., Refetoff, S. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI116474 publisherName Journal of Clinical Investigation title Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene: analysis of 15 families. mimNumber 190160 referenceNumber 78 publisherAbbreviation JCI pubmedID 8514853 source J. Clin. Invest. 91: 2408-2415, 1993. authors Weiss, R. E., Weinberg, M., Refetoff, S. pubmedImages false publisherUrl http://www.jci.org articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=16464943 publisherName HighWire Press title A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone. mimNumber 190160 referenceNumber 79 publisherAbbreviation HighWire pubmedID 16464943 source J. Clin. Endocr. Metab. 91: 1887-1895, 2006. authors Wu, S. Y., Cohen, R. N., Simsek, E., Senses, D. A., Yar, N. E., Grasberger, H., Noel, J., Refetoff, S., Weiss, R. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9141558 publisherName HighWire Press title Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3-prime-triiodothyronine binding affinity. mimNumber 190160 referenceNumber 80 publisherAbbreviation HighWire pubmedID 9141558 source J. Clin. Endocr. Metab. 82: 1608-1614, 1997. authors Yagi, H., Pohlenz, J., Hayashi, Y., Sakurai, A., Refetoff, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=11435616 publisherName HighWire Press title Isoform-specific transcriptional regulation by thyroid hormone receptors: hormone-independent activation operates through a steroid receptor mode of coactivator interaction. mimNumber 190160 referenceNumber 81 publisherAbbreviation HighWire pubmedID 11435616 source Molec. Endocr. 15: 1170-1185, 2001. authors Yang, Z., Privalsky, M. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI116058 publisherName Journal of Clinical Investigation title New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone. mimNumber 190160 referenceNumber 82 publisherAbbreviation JCI pubmedID 1430208 source J. Clin. Invest. 90: 1825-1831, 1992. authors Yen, P. M., Sugawara, A., Refetoff, S., Chin, W. W. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI28598 publisherName Journal of Clinical Investigation title Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta-receptor inhibits mitotic progression. mimNumber 190160 referenceNumber 83 publisherAbbreviation JCI pubmedID 17039256 source J. Clin. Invest. 116: 2972-2984, 2006. authors Ying, H., Furuya, F., Zhao, L., Araki, O., West, B. L., Hanover, J. A., Willingham, M. C., Cheng, S. pubmedImages true publisherUrl http://www.jci.org seeAlso Dobrovic et al. (1988); Refetoff et al. (1972); Sap et al. (1986); Spurr et al. (1984)

entryList

entry status live phenotypeMapList phenotypeMap geneSymbols CA2 sequenceID 6478 chromosomeLocationStart 86376130 chromosomeSort 319 phenotypeMimNumber 259730 chromosomeSymbol 8 mimNumber 611492 geneInheritance None phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 259700 phenotypeMappingKey 3 phenotype Osteopetrosis, autosomal recessive 3, with renal tubular acidosis computedCytoLocation 8q21.2 cytoLocation 8q22 transcript uc003ydk.2 chromosomeLocationEnd 86393720 chromosome 8 contributors Marla J. F. O'Neill - reorganized : 10/3/2007 Marla J. F. O'Neill - updated : 10/3/2007 Marla J. F. O'Neill - updated : 1/5/2005 Victor A. McKusick - updated : 4/16/1998 Ada Hamosh - updated : 7/10/1997 Victor A. McKusick - updated : 6/18/1997 Moyra Smith - updated : 3/13/1996 Orest Hurko - updated : 8/15/1995 externalLinks cmgGene false mgiHumanDisease true nextGxDx false omiaIDs 000755;;Osteopetrosis orphanetDiseases 2785;;555;;Osteopetrosis with renal tubular acidosis dermAtlas false swissProtIDs P00918 gtr true possumSyndromes 4170;;Osteopetrosis, renal tubular acidosis ordrDiseases 4154;;Osteopetrosis autosomal recessive 3 snomedctIDs 254122007 umlsIDs C0345407 geneTests false geneticAllianceIDs 5479 geneticsHomeReferenceIDs condition;;osteopetrosis;;osteopetrosis clinicalSynopsisExists true mimNumber 259730 dateCreated Wed, 04 Jun 1986 03:00:00 EDT clinicalSynopsis headAndNeckTeethExists false headAndNeckNeckExists false skinNailsHairSkinHistologyExists false oldFormatExists true skinNailsHairSkinExists false miscellaneousExists false headAndNeckEyesExists false abdomenBiliaryTractExists false skinNailsHairExists false headAndNeckMouthExists false genitourinaryBladderExists false skeletalSkullExists false chestDiaphragmExists false neurologicCentralNervousSystemExists false immunologyExists false genitourinaryExists false skeletalPelvisExists false neurologicBehavioralPsychiatricManifestationsExists false molecularBasisExists false growthExists false genitourinaryUretersExists false abdomenGastrointestinalExists false skeletalHandsExists false skeletalExists false skeletalFeetExists false creationDate Undefined genitourinaryExternalGenitaliaFemaleExists false genitourinaryInternalGenitaliaFemaleExists false growthOtherExists false growthWeightExists false laboratoryAbnormalitiesExists false voiceExists false metabolicFeaturesExists false growthHeightExists false endocrineFeaturesExists false skinNailsHairNailsExists false neurologicExists false prenatalManifestationsMovementExists false abdomenSpleenExists false respiratoryExists false hematologyExists false prenatalManifestationsDeliveryExists false skinNailsHairHairExists false prenatalManifestationsPlacentaAndUmbilicalCordExists false genitourinaryInternalGenitaliaMaleExists false genitourinaryExternalGenitaliaMaleExists false headAndNeckExists false neurologicPeripheralNervousSystemExists false cardiovascularHeartExists false editHistory Undefined respiratoryLungExists false abdomenExists false headAndNeckFaceExists false skeletalLimbsExists false cardiovascularExists false cardiovascularVascularExists false headAndNeckHeadExists false abdomenPancreasExists false headAndNeckEarsExists false genitourinaryKidneysExists false respiratoryNasopharynxExists false respiratoryAirwaysExists false skeletalSpineExists false chestRibsSternumClaviclesAndScapulaeExists false neoplasiaExists false abdomenLiverExists false chestBreastsExists false prenatalManifestationsMaternalExists false skinNailsHairSkinElectronMicroscopyExists false inheritanceExists false prenatalManifestationsExists false headAndNeckNoseExists false abdomenExternalFeaturesExists false chestExists false prenatalManifestationsAmnioticFluidExists false respiratoryLarynxExists false chestExternalFeaturesExists false muscleSoftTissueExists false oldFormat Limbs Diaphyseal sclerosis {SNOMEDCT:34643004} {ICD10CM:Q78.3} {UMLS:C0011989} {HPO HP:0003034 UMLS:C0011989,C0029464}; Neuro Basal ganglion calcification {ICD10CM:G23.8} {UMLS:C1389280} {HPO HP:0002135 UMLS:C1389280}; Normal intelligence or mental retardation; Inheritance Autosomal recessive {SNOMEDCT:258211005} {UMLS:C0441748} {HPO HP:0000007}; Misc Onset in first 2 years with fractures; Lab Renal tubular acidosis, type I {SNOMEDCT:86210009,236461000} {UMLS:C0259810} {HPO HP:0008341}; Elevated serum acid phosphatase {UMLS:C1839866} {HPO HP:0003148 UMLS:C1839866}; Osteoclasts fail to form 'ruffled membranes' characteristic of active bone resorbing cells; Periodic hypokalemic paresis {HPO HP:0008153}; Carbonic anhydrase II defect; Heme Anemia {UMLS:C1000483} {HPO HP:0001903 UMLS:C0162119,C1000483}; Extramedullary hematopoiesis {SNOMEDCT:42952007} {UMLS:C2613439} {HPO HP:0001978 UMLS:C0018952,C1292120}; Skel Osteosclerosis {SNOMEDCT:49347007} {ICD10CM:Q78.2} {UMLS:C0029464} {HPO HP:0011001 UMLS:C1865344}; Growth Short stature {UMLS:C2919142} {HPO HP:0004322 UMLS:C2237041}; HEENT Cranial hyperostosis {HPO HP:0004437}; Dental malocclusion {SNOMEDCT:47944004} {ICD10CM:M26.4} {ICD9CM:524.4} {UMLS:C0024636} {HPO HP:0000689 UMLS:C0024636}; Visual impairment from optic nerve compression; GI Hepatosplenomegaly {SNOMEDCT:36760000} {ICD10CM:R16.2} {UMLS:C0019214} {HPO HP:0001433 UMLS:C0019214}; prefix # titles alternativeTitles OSTEOPETROSIS WITH RENAL TUBULAR ACIDOSIS;; CARBONIC ANHYDRASE II DEFICIENCY;; GUIBAUD-VAINSEL SYNDROME;; MARBLE BRAIN DISEASE preferredTitle OSTEOPETROSIS, AUTOSOMAL RECESSIVE 3; OPTB3 phenotypeMapExists true textSectionList textSection textSectionTitle Text textSectionContent A number sign (#) is used with this entry because this form of autosomal recessive osteopetrosis is caused by homozygous or compound heterozygous mutation in the gene encoding carbonic anhydrase II (CA2; {611492}) on chromosome 8q22. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 ({259700}). textSectionName text textSectionTitle Clinical Features textSectionContent {15:Sly et al. (1972)} described 3 sisters, aged 22, 17, and 15 years, born to normal unrelated North American parents, with a form of osteopetrosis distinct from both the malignant form (see OPTB1, {259700}) and the benign autosomal dominant form (see OPTA1, {607634}). The disorder was manifest in the first 2 years because of fractures. Other features were short stature, mental retardation, dental malocclusion, and visual impairment from optic nerve compression. Mild anemia in infancy improved later and radiographic features of osteopetrosis improved some at puberty. Serum acid phosphatase was elevated and electrolyte changes suggested mild tubular acidosis. {24:Whyte et al. (1980)} provided a definitive report of these sibs. During adolescence basal ganglion calcification developed in 2. Renal tubular acidosis (type I) was diagnosed in each in early adulthood. Electron microscopy of bone suggested that osteoclasts failed to form 'ruffled membranes' characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations. {7:Guibaud et al. (1972)} described 2 brothers with renal tubular acidosis and mild osteopetrosis. The unaffected parents, from North Africa, were cousins. {11:Ohlsson et al. (1980)} observed the syndrome, which they referred to as marble brain disease, in children of 3 Saudi families. They had striking facial similarities and cerebral calcifications. {4:Bourke et al. (1981)} observed this syndrome in 2 Kuwaiti Bedouin sibs. One sib showed basal ganglion calcification and mental subnormality. The major clinical manifestation in both was periodic hypokalemic paresis. Consanguinity was present in 9 of 12 pedigrees reported by {16:Sly et al. (1985)}. More than half the known cases have been in families from Kuwait, Saudi Arabia, and North Africa. {10:Ohlsson et al. (1986)} described the findings in 4 new Saudi Arabian cases from 2 families, including the first description in a neonate. They reviewed the 17 previously reported cases. {5:Cochat et al. (1987)} added a case and reviewed the findings in 30 reported patients. {1:Al Rajeh et al. (1988)} described 2 affected sisters in a Saudi Arabian family. {19:Strisciuglio et al. (1990)} described 3 affected Italian sibs, the offspring of first cousins once removed. They had osteopetrosis with fractures and severe mental retardation. Whereas most previous patients had a mixed (proximal and distal) renal tubular acidosis, these patients had only proximal tubular acidosis. {2:Aramaki et al. (1993)} reported in detail the findings in 3 unrelated Japanese patients with CA II deficiency. Two of the 3 were born of first-cousin parents. All exhibited poor activity and poor appetite in the neonatal period and then developed psychomotor retardation. Two of them were diagnosed as having osteopetrosis at 10 months and 36 years of age, respectively, and the third as having osteomalacia at 28 years of age. All 3 had recurrent episodes of muscle weakness. Their parents exhibited approximately 50% normal levels of CA II activity in protein. The development of osteomalacia was considered to be related to the renal tubular acidosis. textSectionName clinicalFeatures textSectionTitle Pathogenesis textSectionContent {14:Sly et al. (1983)} were prompted to examine carbonic anhydrase (CA) in this disorder because sulfonamide inhibitors of CA can produce renal tubular acidosis and block the parathormone-induced release of calcium from bone. Although the relationship of CA deficiency to brain calcification was unclear, it was known that one CA, CA II, is present in brain and that CA inhibitors reduce CSF production and affect electric activity of the brain. CA II is the one of the 3 CAs that is expressed in both brain and kidney. Since it also is expressed in the red cell, {14:Sly et al. (1983)} could study CA II in this tissue of their patients; they found very low levels in affected persons and intermediate levels in obligatory heterozygotes. The results indicate a role of CA II in osteoclast function and bone resorption. The RTA in this disorder is a hybrid of a mild proximal and prominent distal type. CA II is the only cytosolic isozyme in the kidney. Red cell CA I ({114800}) has been found to be normal in distal RTA. textSectionName pathogenesis textSectionTitle Population Genetics textSectionContent {6:Fathallah et al. (1997)} traced the origin of this disorder in 24 Tunisian families with CA II deficiency. All were descended from a common ancestor who emigrated from the Arabic Peninsula to North Africa in the 10th century. textSectionName populationGenetics textSectionTitle Molecular Genetics textSectionContent {22,23:Venta et al. (1990, 1991)} sequenced the CA2 gene in a patient with osteopetrosis and renal tubular acidosis from the consanguineous Belgian family first described by {21:Vainsel et al. (1972)} and identified homozygosity for a missense mutation (H107Y; {611492.0004}). {12:Roth et al. (1992)} analyzed the molecular basis of carbonic anhydrase II deficiency in the American family in which the association of CA2 deficiency with a clinical syndrome was first recognized by {15:Sly et al. (1972)}. The 3 affected sisters were found to be compound heterozygotes for a maternally inherited H107Y mutation ({611492.0004}) and a paternally inherited splice site mutation ({611492.0005}). {12:Roth et al. (1992)} suggested that residual activity of the H107Y mutant enzyme, demonstrated in expression studies in bacteria, might explain the absence of mental retardation and relatively mild phenotype in affected members of this family. {9:Hu et al. (1992)} pointed out that of the 39 reported cases of carbonic anhydrase deficiency syndrome, 72% were patients from North Africa and the Middle East countries, most, if not all, of whom were of Arabic descent. They showed that members of 6 unrelated Arabic kindreds were in 5 instances homozygous and in 1 instance heterozygous for a splice site mutation in intron 3 of the CA2 gene ({611492.0006}). Called the 'Arabic mutation,' it introduces a new Sau3A1 restriction site useful in PCR-based diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of patients with the Arabic mutation from that of American and Belgian patients with the H107Y mutation. In a 23-year-old Japanese woman previously reported by {2:Aramaki et al. (1993)} ('patient 1' of pedigree A) with carbonic anhydrase II deficiency, osteopetrosis, renal tubular acidosis, symmetrical cerebral calcification, and mental retardation, {17:Soda et al. (1995)} found a Y40X mutation in exon 2 of the CA2 gene resulting from a TAT-to-TAG transversion. {18:Soda et al. (1996)} identified the H107Y mutation in 2 unrelated Japanese patients previously described by {2:Aramaki et al. (1993)}, both born of consanguineous parents, who had osteopetrosis and renal tubular acidosis as well as severe mental retardation. The authors stated that the basis for the more severe expression of the H107Y mutation, including mental retardation, in Japanese patients was unclear. {8:Hu et al. (1997)} identified 7 novel mutations in the CA2 gene in patients with osteopetrosis and mental retardation or developmental delay. All but 1 pair of Mexican sibs had renal tubular acidosis also. {3:Borthwick et al. (2003)} described 2 consanguineous Turkish kindreds with distal RTA and osteopetrosis. In affected members of 1 kindred, the authors identified homozygosity for a frameshift mutation in the CA2 gene ({611492.0008}). The authors excluded defects in CA2 in the other kindred, in which the proband had RTA and osteopetrosis but his sister manifested only RTA with sensorineural hearing loss and never developed osteopetrosis. In this kindred, {3:Borthwick et al. (2003)} found that the osteopetrosis ({259700}) was the result of a homozygous deletion in the TCIRG1 gene ({604592.0007}), whereas the distal RTA with hearing loss ({267300}) was the result of a homozygous mutation in the ATP6V1B1 gene ({192132.0005}). {3:Borthwick et al. (2003)} concluded that coinheritance of these 2 rare recessive disorders created a phenocopy of CA2A deficiency in this kindred, and commented that this case illustrates the importance of clinical characterization of all affected members of a kindred. textSectionName molecularGenetics epochCreated 518252400 editHistory alopez : 02/19/2013 carol : 10/10/2007 carol : 10/3/2007 carol : 10/3/2007 terry : 4/4/2005 carol : 1/5/2005 carol : 3/17/2004 carol : 2/2/2004 carol : 3/1/2000 carol : 3/1/2000 carol : 9/29/1999 carol : 9/28/1998 dkim : 9/10/1998 dholmes : 5/11/1998 carol : 5/2/1998 terry : 4/16/1998 alopez : 8/26/1997 alopez : 7/10/1997 alopez : 7/10/1997 jenny : 6/23/1997 mark : 6/18/1997 terry : 4/15/1996 mark : 3/13/1996 terry : 3/13/1996 mark : 3/13/1996 mark : 7/6/1995 pfoster : 8/17/1994 terry : 7/18/1994 jason : 7/12/1994 phenotypicSeriesExists true creationDate Victor A. McKusick : 6/4/1986 epochUpdated 1361260800 dateUpdated Tue, 19 Feb 2013 03:00:00 EST referenceList reference articleUrl http://www.thieme-connect.com/DOI/DOI?10.1055/s-2008-1052422 publisherName Georg Thieme Verlag Stuttgart, New York title The syndrome of osteopetrosis, renal acidosis and cerebral calcification in two sisters. mimNumber 259730 referenceNumber 1 publisherAbbreviation Thieme pubmedID 3221988 source Neuropediatrics 19: 162-165, 1988. authors Al Rajeh, S., El Mouzan, M. I., Ahlberg, A., Ozaksoy, D. pubmedImages false publisherUrl http://www.thieme.com title Carbonic anhydrase II deficiency in three unrelated Japanese patients. mimNumber 259730 referenceNumber 2 pubmedID 8127074 source J. Inherit. Metab. Dis. 16: 982-990, 1993. authors Aramaki, S., Yoshida, I., Yoshino, M., Kondo, M., Sato, Y., Noda, K., Jo, R., Okue, A., Sai, N., Yamashita, F. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=12566520 publisherName HighWire Press title A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. mimNumber 259730 referenceNumber 3 publisherAbbreviation HighWire pubmedID 12566520 source J. Med. Genet. 40: 115-121, 2003. authors Borthwick, K. J., Kandemir, N., Topaloglu, R., Kornak, U., Bakkaloglu, A., Yordam, N., Ozen, S., Mocan, H., Shah, G. N., Sly, W. S., Karet, F. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Renal tubular acidosis and osteopetrosis in siblings. mimNumber 259730 referenceNumber 4 pubmedID 7312081 source Nephron 28: 268-272, 1981. authors Bourke, E., Delaney, V. B., Mosawi, M., Reavey, P., Weston, M. pubmedImages false title Deficit en anhydrase carbonique II: osteopetrose, acidose renale tubulaire et calcifications intracraniennes. Revue de la literature a'partir de trois observation. mimNumber 259730 referenceNumber 5 pubmedID 3112731 source Pediatrie 42: 121-128, 1987. authors Cochat, P., Loras-Duclaux, I., Guibaud, P. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/7099005/70990634.htm publisherName Springer title Carbonic anhydrase II (CA II) deficiency in Maghrebian patients: evidence for founder effect and genomic recombination at the CA II locus. mimNumber 259730 referenceNumber 6 publisherAbbreviation Springer pubmedID 9150731 source Hum. Genet. 99: 634-637, 1997. authors Fathallah, D. M., Bejaoui, M., Lepaslier, D., Chater, K., Sly, W. S., Dellagi, K. pubmedImages false publisherUrl http://www.springeronline.com/ title Osteopetrose et acidose renale tubulaire. Deux cas de cette association dans une fratrie. mimNumber 259730 referenceNumber 7 pubmedID 4661410 source Arch. Franc. Pediat. 29: 269-286, 1972. authors Guibaud, P., Larbre, F., Freycon, M. T., Genoud, J. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5 publisherName John Wiley & Sons, Inc. title Seven novel mutations in carbonic acid anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. mimNumber 259730 referenceNumber 8 publisherAbbreviation Wiley pubmedID 9143915 source Hum. Mutat. 9: 383-387, 1997. authors Hu, P. Y., Lim, E. J., Ciccolella, J., Strisciuglio, P., Sly, W. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. mimNumber 259730 referenceNumber 9 pubmedID 1301935 source Hum. Mutat. 1: 288-292, 1992. authors Hu, P. Y., Roth, D. E., Skaggs, L. A., Venta, P. J., Tashian, R. E., Guibaud, P., Sly, W. S. pubmedImages false title Carbonic anhydrase II deficiency syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. mimNumber 259730 referenceNumber 10 pubmedID 3081869 source Pediatrics 77: 371-381, 1986. authors Ohlsson, A., Cumming, W. A., Paul, A., Sly, W. S. pubmedImages false title Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. mimNumber 259730 referenceNumber 11 pubmedID 7358236 source Dev. Med. Child Neurol. 22: 72-84, 1980. authors Ohlsson, A., Stark, G., Sakati, N. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1542674 publisherName HighWire Press title Molecular basis of human carbonic anhydrase II deficiency. mimNumber 259730 referenceNumber 12 publisherAbbreviation HighWire pubmedID 1542674 source Proc. Nat. Acad. Sci. 89: 1804-1808, 1992. authors Roth, D. E., Venta, P. J., Tashian, R. E., Sly, W. S. pubmedImages false publisherUrl http://highwire.stanford.edu source New York: McGraw-Hill (pub.) (6th ed.) II: 1989. Pp. 2857-2866. mimNumber 259730 authors Sly, W. S. title The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. : The Metabolic Basis of Inherited Disease. referenceNumber 13 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6405388 publisherName HighWire Press title Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. mimNumber 259730 referenceNumber 14 publisherAbbreviation HighWire pubmedID 6405388 source Proc. Nat. Acad. Sci. 80: 2752-2756, 1983. authors Sly, W. S., Hewett-Emmett, D., Whyte, M. P., Yu, Y.-S. L., Tashian, R. E. pubmedImages false publisherUrl http://highwire.stanford.edu source Am. J. Hum. Genet. 24: 34A, 1972. mimNumber 259730 authors Sly, W. S., Lang, R., Avioli, L., Haddad, J., Lubowitz, H., McAlister, W. title Recessive osteopetrosis: new clinical phenotype. (Abstract) referenceNumber 15 articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198507183130302?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. mimNumber 259730 referenceNumber 16 publisherAbbreviation ATYPON pubmedID 3925334 source New Eng. J. Med. 313: 139-145, 1985. authors Sly, W. S., Whyte, M. P., Sundaram, V., Tashian, R. E., Hewett-Emmett, D., Guibaud, P., Vainsel, M., Baluarte, H. J., Gruskin, A., Al-Mosawi, M., Sakati, N., Ohlsson, A. pubmedImages false publisherUrl http://www.atypon.com/ title Carbonic anhydrase II deficiency in a Japanese patient produced by a nonsense mutation (TAT-to-TAG) at tyr-40 in exon 2, (Y40X). mimNumber 259730 referenceNumber 17 pubmedID 7627193 source Hum. Mutat. 5: 348-350, 1995. authors Soda, H., Yukizane, S., Yoshida, I., Aramaki, S., Kato, H. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/6097004/60970435.htm publisherName Springer title A point mutation in exon 3 (his107-to-tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. mimNumber 259730 referenceNumber 18 publisherAbbreviation Springer pubmedID 8834238 source Hum. Genet. 97: 435-437, 1996. authors Soda, H., Yukizane, S., Yoshida, I., Koga, Y., Aramaki, S., Kato, H. pubmedImages false publisherUrl http://www.springeronline.com/ title Variable clinical presentation of carbonic anhydrase deficiency: evidence for heterogeneity? mimNumber 259730 referenceNumber 19 pubmedID 2107079 source Europ. J. Pediat. 149: 337-340, 1990. authors Strisciuglio, P., Sartorio, R., Pecoraro, C., Lotito, F., Sly, W. S. pubmedImages false title Carbonic anhydrase II deficiency: diagnosis and carrier detection using differential enzyme inhibition and inactivation. mimNumber 259730 referenceNumber 20 pubmedID 3080873 source Am. J. Hum. Genet. 38: 125-136, 1986. authors Sundaram, V., Rumbolo, P., Grubb, J., Strisciuglio, P., Sly, W. S. pubmedImages false title Osteopetrosis associated with proximal and distal tubular acidosis. mimNumber 259730 referenceNumber 21 pubmedID 5041390 source Acta Paediat. Scand. 61: 429-434, 1972. authors Vainsel, M., Fondu, P., Cadranel, S., Rocmans, C., Gepts, W. pubmedImages false source Am. J. Hum. Genet. 47 (suppl.): A168, 1990. mimNumber 259730 authors Venta, P. J., Welty, R. J., Johnson, T. H., Tashian, R. E. title Human carbonic anhydrase II deficiency syndrome in a Belgium family appears to be caused by a destabilizing amino acid substitution (107his-to-tyr). (Abstract) referenceNumber 22 title Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107his-to-tyr): complete structure of the normal human CA II gene. mimNumber 259730 referenceNumber 23 pubmedID 1928091 source Am. J. Hum. Genet. 49: 1082-1090, 1991. authors Venta, P. J., Welty, R. J., Johnson, T. M., Sly, W. S., Tashian, R. E. pubmedImages false title Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. mimNumber 259730 referenceNumber 24 pubmedID 7386510 source Am. J. Med. 69: 64-74, 1980. authors Whyte, M. P., Murphy, W. A., Fallon, M. D., Sly, W. S., Teitelbaum, S. L., McAlister, W. H., Avioli, L. V. pubmedImages false seeAlso Sly (1989); Sundaram et al. (1986)

entryList

entry status live allelicVariantExists true epochCreated 1046073600 geneMap geneSymbols ARSA sequenceID 14342 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 607574 phenotypeInheritance Autosomal recessive phenotype Metachromatic leukodystrophy phenotypeMimNumber 250100 chromosomeLocationStart 51061181 chromosomeSort 354 chromosomeSymbol 22 mimNumber 607574 geneInheritance None confidence C mappingMethod S, D geneName Arylsulfatase A mouseMgiID MGI:88077 mouseGeneSymbol Arsa computedCytoLocation 22q13.33 cytoLocation 22q13.31-qter transcript uc003bmz.5 chromosomeLocationEnd 51066600 chromosome 22 contributors George E. Tiller - updated : 5/19/2008 Cassandra L. Kniffin - updated : 7/31/2007 Cassandra L. Kniffin - updated : 6/24/2003 externalLinks mgiIDs MGI:88077 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 313569792,313569794,313569796,313569798,313569790 nbkIDs NBK1130;;Arylsulfatase A Deficiency dermAtlas false hprdIDs 09617 swissProtIDs P15289 zfinIDs ZDB-GENE-050320-118 uniGenes Hs.88251,Hs.731715 refSeqAccessionIDs NG_009260.2 gtr true cmgGene false ensemblIDs ENSG00000100299,ENST00000216124 umlsIDs C1412553 genbankNucleotideSequences 21758734,109451599,190690452,33874702,109451021,123988654,511786510,47678296,24786218,47396359,81206083,194375168,81277901,71514907,23299451,20360364,19175227,30016942,123999168,34367780,190691830,164693216,52235311,148149543,21751422,6862558,220983389,28857,28859,148149544,15762575 geneTests true approvedGeneSymbols ARSA geneIDs 410 proteinSequences 109451022,190690453,33874703,1399961,123988655,52545967,47678297,313569791,194375169,109451600,119593988,30016943,119593989,123999169,190691831,114221,313569793,313569795,220983390,313569797,146229327,189054653,578837689,28858,28860 geneticsHomeReferenceIDs gene;;ARSA;;ARSA clinicalSynopsisExists false mimNumber 607574 allelicVariantList allelicVariant status live name ARYLSULFATASE A PSEUDODEFICIENCY dbSnps rs6151429 text In an individual homozygous for the ARSA pseudodeficiency ({250100}) allele, {19:Gieselmann et al. (1989)} found 2 A-to-G transitions: one changed asn350 to serine, leading to loss of an N-glycosylation site ({607574.0002}). This loss explained the smaller size of ARSA in ARSA pseudodeficient fibroblasts. Introduction of ser350 into normal ARSA cDNA did not affect the rate of synthesis, stability, or catalytic properties of ARSA in stably transfected baby hamster kidney cells, however. The other A-to-G transition changed the first polyadenylation signal downstream of the stop codon from AATAAC to AGTAAC. The latter change caused a severe deficiency of a 2.1-kb RNA species. The deficiency of the 2.1-kb RNA species explained the diminished synthesis of ARSA in pseudodeficiency fibroblasts. The same change was found in 4 unrelated individuals with pseudodeficiency. In those who are homozygous for the pseudodeficiency allele or carry it in heterozygous state with a normal allele, enough arylsulfatase A is synthesized to prevent clinically apparent disease. In combination with other mutant alleles, it may cause metachromatic leukodystrophy. {43:Nelson et al. (1991)} likewise found the A-to-G change at nucleotide 1620 in the first polyadenylation signal of the ARSA gene resulting in loss of its major mRNA species and a greatly reduced level of enzyme activity. This change was found to be closely linked to another A-to-G transition at nucleotide 1049 which changed asparagine-350 to serine but did not affect ARSA activity. The findings of {43:Nelson et al. (1991)} supported the conclusion of {19:Gieselmann et al. (1989)} that the change in nucleotide 1620 is always associated with that at nucleotide 1049. {4:Barth et al. (1994)} stated that the 2 mutations do not always occur together and that at least the N350S mutation may be found alone. The carrier frequency of the ARSA pseudodeficiency mutation in Australia was estimated to be about 20%. {35:Li et al. (1992)} described a polymerase chain reaction (PCR)-based method for genotypically identifying pseudodeficiency. {4:Barth et al. (1994)} used PCR and restriction endonuclease digestion to determine the frequency of A-to-G transitions at bases 1049 (N350S) and 1620 in healthy persons from England. Mutations were found in 24 of 77 screened persons. Two were homozygous for both mutations, 16 were heterozygous for both, 5 were heterozygous for the N350S mutation alone, and 1 was homozygous for the N350S mutation. Study of the 16 persons heterozygous for both mutations showed that in 15 persons both mutations were located on the same chromosome, and in 1 person the mutations were located on different chromosomes. Persons homozygous for both mutations had the lowest activities of ARSA. {22:Harvey et al. (1998)} presented evidence that the combined effect of reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein ({607574.0002}) to the lysosome was estimated to reduce ARSA activity in pseudodeficiency homozygotes to approximately 8% of normal. mutations ARSA, MUTATION IN POLYADENYLATION SIGNAL number 1 clinvarAccessions RCV000020309;;1;;;RCV000003190;;1 status live name ARYLSULFATASE A POLYMORPHISM dbSnps rs2071421 text In a homozygote for ARSA deficiency ({250100}), {19:Gieselmann et al. (1989)} demonstrated that an A-to-G transition in the polyadenylation signal downstream of the stop codon, from AATAAC to AGTAAC, was responsible for the severe deficiency of a 2.1-kb RNA species and the diminished synthesis of ARSA ({607574.0001}). A second mutation, asn350-to-serine, resulting from an A-to-G transition, appeared to be responsible for the small size of ARSA produced by pseudodeficiency fibroblasts because it led to loss of an N-glycosylation site. It was not, however, responsible for the defective synthesis of enzyme. The asn350-to-ser mutation is a polymorphism that does not affect the activity or stability of the enzyme, whereas the other mutation causes the loss of about 90% of ARSA mRNA, which explains the loss of 90% of ARSA crossreacting material and enzyme activity. The 'pseudodeficiency' allele, found in a frequency of approximately 10% in many populations, is associated with 2 A-to-G transitions in cis in the ARSA gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, {44:Ott et al. (1997)} studied 400 individuals in the African, European, Indian, and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varies from 0.01 in Indians and 0.06 in Europeans to 0.21 in East Asians and 0.32 in Africans. The frequencies of both mutations occurring together range from almost nonexistent in the Africans and East Asians, to 0.075 in Europeans and 0.125 in Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and 8 multigeneration families with 6 polymorphism-identifying restriction enzymes showed that, of the 5 haplotypes found in the general population, only 1 was linked to the double mutations. Alleles among the 4 populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans, whose alleles were discordant. These results were considered consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa approximately 100,000 to 200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. mutations ARSA, ASN350SER number 2 clinvarAccessions RCV000078931;;0;;;RCV000020310;;1;;;RCV000003191;;1 status live name METACHROMATIC LEUKODYSTROPHY, JUVENILE dbSnps rs80338815 text In a patient with juvenile-onset metachromatic leukodystrophy ({250100}), {46:Polten et al. (1991)} found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene. Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy. Specifically, a G-to-A transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, {46:Polten et al. (1991)} reported that the clinical picture was that of the late infantile form of metachromatic leukodystrophy. {26:Heinisch et al. (1995)} found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area. {12:Draghia et al. (1997)}, who referred to this mutation as 459+1G-A, cited reports stating that it, and the P426L mutation ({607574.0004}), have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients ({46:Polten et al., 1991}; {3:Barth et al., 1993}). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients ({20:Gieselmann et al., 1994}). {9:Comabella et al. (2001)} reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for this mutation and a 1223C-T transition resulting in a thr408-to-ile (T408I; {607574.0045}) substitution in the ARSA gene. The mutations segregated independently; the unaffected father was a carrier for this mutation and 2 daughters from the proband's second marriage were each carriers for 1 or the other of the mutations. Noting that homozygosity for this mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. In an Italian patient with juvenile-onset metachromatic leukodystrophy, {21:Gomez-Lira et al. (1998)} identified compound heterozygosity for the 459+1G-A and the I179S ({607574.0008}) mutations in the ARSA gene. mutations ARSA, IVS2DS, G-A, +1 number 3 alternativeNames ARYLSULFATASE A, ALLELE I, INCLUDED;; METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED clinvarAccessions RCV000020319;;1;;;RCV000003192;;1;;;RCV000003194;;1;;;RCV000078947;;1 status live name METACHROMATIC LEUKODYSTROPHY, JUVENILE dbSnps rs28940893 text In a patient with juvenile-onset metachromatic leukodystrophy ({250100}), {46:Polten et al. (1991)} found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' ({607574.0003}) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, {46:Polten et al. (1991)} introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). {46:Polten et al. (1991)} determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, {46:Polten et al. (1991)} found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. {12:Draghia et al. (1997)}, cited reports stating that the P426L mutation and a splice site mutation ({607574.0003}) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients ({46:Polten et al., 1991}; {3:Barth et al., 1993}). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients ({20:Gieselmann et al., 1994}). mutations ARSA, PRO426LEU number 4 alternativeNames ARYLSULFATASE A, ALLELE A, INCLUDED;; METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED clinvarAccessions RCV000078940;;1;;;RCV000020314;;1;;;RCV000003197;;1;;;RCV000003196;;1;;;RCV000003195;;1 status live name METACHROMATIC LEUKODYSTROPHY, ADULT dbSnps rs74315455 text In a Japanese patient with adult-type metachromatic leukodystrophy ({250100}), {32:Kondo et al. (1991)} identified a G-to-A transition in exon 2, which resulted in amino acid substitution of aspartic acid for glycine-99. In transient expression studies, COS cells transfected with the mutant cDNA carrying gly99-to-asp did not show increase of ARSA activity, thus confirming that the mutation was the cause of MLD. mutations ARSA, GLY99ASP number 5 clinvarAccessions RCV000020318;;1;;;RCV000003198;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE dbSnps rs74315456 text In a patient with the late infantile form of metachromatic leukodystrophy ({250100}), {18:Gieselmann et al. (1991)} found homozygosity for the mutations characteristic of the arylsulfatase A pseudodeficiency allele but, in addition, a C-to-T transition in exon 2 causing a substitution of phenylalanine for serine-96. {18:Gieselmann et al. (1991)} pointed out the necessity for care in not overlooking a mutation causing severe deficiency associated with the changes of pseudodeficiency. This can be a serious problem since homozygous pseudodeficiency is present in 1 to 2% of the population. mutations ARSA, SER96PHE number 6 clinvarAccessions RCV000078943;;1;;;RCV000003199;;1;;;RCV000020317;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE text {6:Bohne et al. (1991)} demonstrated an 11-bp deletion in exon 8 of one allele of the ARSA gene in a patient with the late infantile form of MLD ({250100}). Although this allele produced normal amounts of mRNA, no arylsulfatase A crossreacting material could be detected in cultured fibroblasts from the patient. The 11-bp deletion was found between nucleotides 2506 and 2516. It caused a frameshift downstream of the codon for amino acid 467. The polypeptide encoded by the mutant allele should be 29 amino acids longer than wildtype ASA. The other allele, which had been inherited from the father, had a splice donor site mutation in exon 7. This allele is known also to generate no ASA polypeptide. Thus, this was another example where absence of ASA polypeptide correlated with the severe late infantile form of MLD. mutations ARSA, 11-BP DEL, EX8 number 7 clinvarAccessions RCV000003200;;1 status live name METACHROMATIC LEUKODYSTROPHY, JUVENILE dbSnps rs74315457 text In a patient with juvenile-onset metachromatic leukodystrophy ({250100}), {14:Fluharty et al. (1991)} identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon. {36:Lugowska et al. (2002)} pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. {36:Lugowska et al. (2002)} stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele ({607574.0001}) who does not present with clinical symptoms of classic MLD. In 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, {21:Gomez-Lira et al. (1998)} identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation ({607574.0008}); the patient with juvenile onset had the common 459+1G-A ({607574.0003}) mutation, and the patient with adult onset had a pro135-to-leu mutation ({607574.0042}). mutations ARSA, ILE179SER number 8 alternativeNames METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED clinvarAccessions RCV000003203;;1;;;RCV000020320;;1;;;RCV000003202;;1 status live name METACHROMATIC LEUKODYSTROPHY, JUVENILE dbSnps rs80338820 text In a patient with juvenile-onset metachromatic leukodystrophy ({250100}), {14:Fluharty et al. (1991)} found compound heterozygosity for a point mutation (see {607574.0008}) and for a G-to-A transition that resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation involved nucleotide 2195, the first nucleotide in intron 7. mutations ARSA, IVS7DS, G-A, +1 number 9 clinvarAccessions RCV000003204;;1;;;RCV000020312;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE-ONSET dbSnps rs74315458 text {31:Kappler et al. (1992)} described an arg84-to-gln mutation in 2 sisters with late-onset metachromatic leukodystrophy ({250100}). One sister developed abnormal behavior at the age of 14 years and was thought to have 'frontal lobe syndrome.' Later she developed peripheral neuropathy and dementia. At the age of 30 she was bedridden. The other sister presented similar biochemical alterations. In spite of cranial CT alterations characteristic of MLD, her clinical status was almost normal when she was 21 years old. At the age of 29 years, she was still without complaints. Both sisters showed residual ARSA activity, further validating the concept that different degrees of residual ARSA activity account for phenotypic variation in this disorder. mutations ARSA, ARG84GLN number 10 clinvarAccessions RCV000020316;;1;;;RCV000003205;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE dbSnps rs74315459 text {33:Kreysing et al. (1993)} described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of 18 months suggestive of MLD ({250100}). Subsequently he lost acquired capabilities such as walking and sitting, developed spastic paresis, and finally became bedridden. He showed episodes of pain attacks occurring several times per hour. Electromyelography showed signs of denervation and decreased nerve conduction velocity. Sural nerve biopsy demonstrated metachromatic granules. The patient had residual ARSA activity of about 10%. Fibroblasts of the patient showed significant sulfatide degradation activity exceeding that of adult MLD patients. One of the mutant alleles was a G-to-A transition in exon 5 causing a gly309-to-ser substitution. Transient expression of this allele resulted in only 13% enzyme activity as compared with the normal. The mutant enzyme was correctly targeted to the lysosomes but was unstable. The other allele showed a deletion of C447 in exon 2, causing a frameshift and a premature stop codon at amino acid position 105 ({607574.0012}). The findings in this patient contrasted with previous results showing that the late infantile type of MLD is always associated with the complete absence of ARSA activity. In this case, the expression of the mutant ARSA protein may have been influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others. mutations ARSA, GLY309SER number 11 clinvarAccessions RCV000003206;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE text See {607574.0011} and {33:Kreysing et al. (1993)}. mutations ARSA, 1-BP DEL, 447C number 12 clinvarAccessions RCV000003201;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315460 text In Muslim Arab patients with severe metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 86 in exon 2. mutations ARSA, GLY86ASP number 13 clinvarAccessions RCV000003207;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs199476371 text In Muslim Arab patients with severe metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing a serine to a leucine at position 96 in exon 2. mutations ARSA, SER96LEU number 14 clinvarAccessions RCV000003208;;1;;;RCV000058959;;0 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315461 text In Japanese and Caucasian patients with metachromatic leukodystrophy ({250100}), {27:Honke et al. (1993)} and {30:Kappler et al. (1994)} identified a G-to-A substitution of the ARSA gene changing a glycine to serine at position 122 in exon 2. The mutation changes the restriction site BalI. mutations ARSA, GLY122SER number 15 clinvarAccessions RCV000078945;;1;;;RCV000003209;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315462 text In Jewish patients with metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing a proline to leucine at position 136 in exon 2. mutations ARSA, PRO136LEU number 16 clinvarAccessions RCV000003210;;1 status live name METACHROMATIC LEUKODYSTROPHY text In Caucasian patients with metachromatic leukodystrophy ({250100}), {33:Kreysing et al. (1993)} identified a 1-bp (C) deletion at position 297 of the coding sequence in exon 2 of the ARSA gene. mutations ARSA, 1-BP DEL, 297C number 17 clinvarAccessions RCV000003211;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315463 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {30:Kappler et al. (1994)} identified a G-to-A substitution of the ARSA gene changing a glycine to aspartic acid at position 154 in exon 3. The mutation changes the restriction site ApaI. mutations ARSA, GLY154ASP number 18 clinvarAccessions RCV000003212;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY dbSnps rs74315464 text In Lebanese patients with arylsulfatase A pseudodeficiency ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-G substitution of the ARSA gene changing a proline to arginine at position 155 in exon 3. mutations ARSA, PRO155ARG number 19 clinvarAccessions RCV000003213;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315465 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {30:Kappler et al. (1994)} identified a C-to-G substitution of the ARSA gene changing a proline to arginine at position 167 in exon 3. mutations ARSA, PRO167ARG number 20 clinvarAccessions RCV000003214;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY dbSnps rs74315466 text In Polynesian patients with arylsulfatase A pseudodeficiency ({250100}), {20:Gieselmann et al. (1994)} reported a G-to-A substitution of the ARSA gene changing an aspartic acid to asparagine at position 169 in exon 3. mutations ARSA, ASP169ASN number 21 clinvarAccessions RCV000003215;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315467 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {1:Barth et al. (1993)} identified a G-to-T substitution of the ARSA gene changing an alanine to valine at position 212 in exon 3. mutations ARSA, ALA212VAL number 22 clinvarAccessions RCV000003216;;2 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315468 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {1:Barth et al. (1993)} identified a C-to-T substitution of the ARSA gene changing an alanine to valine at position 224 in exon 3. mutations ARSA, ALA224VAL number 23 clinvarAccessions RCV000003217;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315469 text In a patient with metachromatic leukodystrophy ({250100}), {8:Caillaud et al. (1993)} identified a C-to-A substitution of the ARSA gene changing a proline to threonine at position 231 in exon 4. mutations ARSA, PRO231THR number 24 clinvarAccessions RCV000003218;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315470 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 244 in exon 4. The mutation changes an SstII restriction site. mutations ARSA, ARG244CYS number 25 clinvarAccessions RCV000003219;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315471 text In Japanese patients with severe metachromatic leukodystrophy ({250100}), {24:Hasegawa et al. (1993)} identified a G-to-A substitution of the ARSA gene changing a glycine to arginine at position 245 in exon 4. The mutation changes an SstII restriction site. mutations ARSA, GLY245ARG number 26 clinvarAccessions RCV000003220;;1;;;RCV000020321;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315472 text In Lebanese patients with severe metachromatic leukodystrophy ({250100}), {23:Harvey et al. (1993)} identified a C-to-T change in exon 4 of the ARSA gene, resulting in a thr274-to-met (T274M) substitution. The T274M allele represented 20% of all alleles among Australian patients with metachromatic leukodystrophy, and about 85% of all alleles among Australian Lebanese affected with the disease. mutations ARSA, THR274MET number 27 clinvarAccessions RCV000003221;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE text In Caucasian patients with severe metachromatic leukodystrophy ({250100}), {45:Pastor-Soler et al. (1994)} identified a G-to-A transition of the ARSA gene at nucleotide 848+1 (which is the first nucleotide of the donor splice site) of intron 4, resulting in abnormal splicing. This mutation causes instability of the arylsulfatase A mRNA and was found in all alleles of Navajo Indians patients with late infantile metachromatic leucodystrophy. mutations ARSA, IVS4DS, G-A, +1 number 28 clinvarAccessions RCV000003222;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315473 text In Caucasian patients with metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 288 in exon 5. mutations ARSA, ARG288CYS number 29 clinvarAccessions RCV000003223;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315474 text In Saudi Arabian patients with severe metachromatic leukodystrophy ({250100}), {1:Barth et al. (1993)} identified a C-to-A substitution of the ARSA gene changing a serine to tyrosine at position 295 in exon 5. mutations ARSA, SER295TYR number 30 clinvarAccessions RCV000003224;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY text In Indian patients with arylsulfatase A pseudodeficiency ({250100}), {20:Gieselmann et al. (1994)} reported a G-to-T substitution of the last nucleotide of ARSA exon 5, changing a glycine to cysteine at position 325 and concomitantly resulting in aberrant splicing of arylsulfatase A mRNA. mutations ARSA, IVS5DS, G-T, -1, GLY325CYS number 31 clinvarAccessions RCV000003225;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315475 text In Caucasian patients with severe metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported an A-to-T substitution of the ARSA gene changing an aspartic acid to valine at position 335 in exon 6. mutations ARSA, ASP335VAL number 32 clinvarAccessions RCV000003226;;1 status live name METACHROMATIC LEUKODYSTROPHY, SEVERE dbSnps rs74315476 text In Christian Arab patients with severe metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 370 in exon 7. mutations ARSA, ARG370TRP number 33 clinvarAccessions RCV000078933;;1;;;RCV000003227;;1 status live name METACHROMATIC LEUKODYSTROPHY, MILD dbSnps rs74315477 text In Jewish patients with mild metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a G-to-A substitution of the ARSA gene changing an arginine to glutamine at position 370 in exon 7. mutations ARSA, ARG370GLN number 34 clinvarAccessions RCV000003228;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY, SEVERE dbSnps rs74315478 text In Habbanite Jewish patients with severe arylsulfatase A pseudodeficiency ({250100}), {53:Zlotogora et al. (1994)} identified a C-to-T substitution of the ARSA gene changing a proline to leucine at position 377 in exon 7. This mutation has a high frequency among the small population of Habbanite Jews (1 in 75 live births). mutations ARSA, PRO377LEU number 35 clinvarAccessions RCV000003229;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY, INTERMEDIATE dbSnps rs74315479 text In Caucasian patients with intermediate arylsulfatase A pseudodeficiency ({250100}), {4:Barth et al. (1994)} identified a G-to-A substitution of the ARSA gene changing a glutamic acid to lysine at position 382 in exon 7. mutations ARSA, GLU382LYS number 36 clinvarAccessions RCV000078936;;1;;;RCV000003230;;1 status live name METACHROMATIC LEUKODYSTROPHY dbSnps rs74315480 text In Indian patients with metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-T substitution of the ARSA gene changing an arginine to tryptophan at position 390 in exon 7. mutations ARSA, ARG390TRP number 37 clinvarAccessions RCV000003231;;1 status live name METACHROMATIC LEUKODYSTROPHY text In Polynesian patients with metachromatic leukodystrophy ({250100}), {20:Gieselmann et al. (1994)} reported an in frame deletion of 3 bp of the ARSA gene corresponding to codon 398 (TTC) in exon 7. The mutation causes a deletion of phenylalanine at position 398. mutations ARSA, 3-BP DEL, PHE398DEL number 38 clinvarAccessions RCV000003232;;1 status live name METACHROMATIC LEUKODYSTROPHY, MILD dbSnps rs74315481 text In Japanese patients with mild metachromatic leukodystrophy ({250100}), {25:Hasegawa et al. (1994)} identified a C-to-T substitution of the ARSA gene changing a threonine to isoleucine at position 409 in exon 8. mutations ARSA, THR409ILE number 39 clinvarAccessions RCV000020313;;1;;;RCV000003233;;1 status live name ARYLSULFATASE A PSEUDODEFICIENCY dbSnps rs74315482 text In Caucasian patients with arylsulfatase A pseudodeficiency ({250100}), {20:Gieselmann et al. (1994)} reported a C-to-A substitution at nucleotide 1456 in ARSA exon 8, resulting in a stop codon at position 486. mutations ARSA, GLN486TER number 40 clinvarAccessions RCV000003234;;1 status moved number 41 name MOVED TO 607574.0008 movedTo 607574.0008 status live name METACHROMATIC LEUKODYSTROPHY, ADULT dbSnps rs121434215 text In an Italian patient with adult-onset metachromatic leukodystrophy ({250100}), {21:Gomez-Lira et al. (1998)} identified compound heterozygosity for mutations in the ARSA gene: the previously described I179S mutation ({607574.0008}) and a 556T-C transition in exon 2 resulting in a leu135-to-pro substitution. In an erratum, the authors stated that this was a 553T-C transition, according to the nomenclature of {20:Gieselmann et al. (1994)}, and results in a pro135-to-leu (P135L) substitution. mutations ARSA, PRO135LEU number 42 clinvarAccessions RCV000003235;;1 status live name METACHROMATIC LEUKODYSTROPHY, ADULT dbSnps rs28940894 text {13:Felice et al. (2000)} reported a 22-year-old Asian Indian man with arylsulfatase deficiency ({250100}), born of consanguineous parents, who presented with acute left hand weakness. Nerve conduction studies showed demyelinating polyneuropathy. Cognitive function was normal, and no leukodystrophy was found on neuroimaging. The patient was found to be homozygous for a 1505A-C transition in exon 5 of the ARSA gene, resulting in a thr286-to-pro substitution. mutations ARSA, THR286PRO number 43 clinvarAccessions RCV000003236;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE dbSnps rs74315483 text In a patient with late infantile metachromatic leukodystrophy ({250100}), {48:Regis et al. (2002)} found a glu253-to-lys (E253K) amino acid substitution due to a G-to-A transition in the ARSA gene. This mutation, which occurred with the T391S polymorphism on the same allele, was in compound heterozygosity with P426L ({607574.0004}) and the N350S ({607574.0002}) and *96A-G pseudodeficiency mutations on the other. mutations ARSA, GLU253LYS number 44 clinvarAccessions RCV000003237;;1 status live name METACHROMATIC LEUKODYSTROPHY, ADULT dbSnps rs28940895 text {9:Comabella et al. (2001)} reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy ({250100}) presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for 2 mutations in the ARSA gene: a G-A transition at IVS2 ({607574.0003}) and a 1223C-T transition resulting in a thr408-to-ile (T408I) substitution. The mutations segregated independently; the unaffected father was a carrier for the IVS2 mutation and 2 daughters from the proband's second marriage were each carriers for 1 or the other of the mutations. Noting that homozygosity for the IVS2 mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. mutations ARSA, THR408ILE number 45 clinvarAccessions RCV000003238;;1 status live name METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE dbSnps rs74315484 text In a Portuguese patient with severe late infantile MLD ({250100}), {38,40:Marcao et al. (1999, 2003)} identified a homozygous missense mutation in the ARSA gene, resulting in a cys300-to-phe (C300F) substitution. Transfection experiments with C300F cDNA demonstrated a reduction of ARSA enzyme activity to less than 1% of wildtype, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, {39:Marcao et al. (2003)} showed that the C300F mutation strongly interfered with the octamerization process of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. mutations ARSA, CYS300PHE number 46 clinvarAccessions RCV000058989;;0;;;RCV000003239;;1 status live name METACHROMATIC LEUKODYSTROPHY, JUVENILE dbSnps rs74315485 text In a patient with juvenile MLD ({250100}), {38,40:Marcao et al. (1999, 2003)} identified compound heterozygosity for a P426L ({607574.0004}) and a pro425-to-thr (P425T) mutation in the ARSA gene. Transfection experiments with P425T cDNA demonstrated residual ARSA enzyme activity of about 10% of normal, and resulted in more rapid enzyme degradation in lysosomes. Using sedimentation analysis of the mutated protein, {39:Marcao et al. (2003)} showed that the P425L mutation resulted in a modest reduction of the octamerization capacity of ARSA at low pH, which may be related to the reduced lysosomal half-life of the enzyme. mutations ARSA, PRO425THR number 47 clinvarAccessions RCV000003240;;1 prefix * titles alternativeTitles CEREBROSIDE-SULFATASE;; CEREBROSIDE 3-SULFATASE preferredTitle ARYLSULFATASE A; ARSA textSectionList textSection textSectionTitle Description textSectionContent The ARSA gene encodes the lysosomal enzyme arylsulfatase A ({EC 3.1.6.8}). textSectionName description textSectionTitle Cloning textSectionContent {51:Stein et al. (1989)} cloned and sequenced a full-length cDNA for human arylsulfatase A. The predicted amino acid sequence comprised 507 residues, including a putative signal peptide of 18 residues. The sequence contains 3 potential N-glycosylation sites. The cDNA hybridized to 2.0- and 3.9-kb species in RNA from human fibroblasts and human liver. {34:Kreysing et al. (1990)} found that 3 different mRNA species of 2.1, 3.7, and 4.8 kb are transcribed from the gene and probably arise from the use of different polyadenylation signals. textSectionName cloning textSectionTitle Biochemical Features textSectionContent {37:Lukatela et al. (1998)} determined the crystal structure of ARSA at 2.1 angstrom resolution. The core of the enzyme consists of 2 beta-pleated sheets, linked by several hydrogen bonds and 1 disulfide bridge. The large central beta-pleated sheet is associated with several helices on each side, resembling bacterial alkaline phosphatase. The quaternary structure of ARSA is highly pH dependent and oscillates between 2 states: at neutral pH, it is predominantly dimeric, and at lysosomal acid pH, it is predominantly a homo-octamer, composed of 4 dimers arranged in a ring-like structure. The dimer-octamer equilibrium is regulated by deprotonation-protonation of glu424. textSectionName biochemicalFeatures textSectionTitle Gene Structure textSectionContent {34:Kreysing et al. (1990)} determined that the ARSA gene contains 8 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent By somatic cell hybridization methods, {11:DeLuca et al. (1979)} assigned arylsulfatases A and B ({611542}) to chromosome 22 and 5, respectively. Using somatic cell hybrids, {28:Hors-Cayla et al. (1979)} confirmed the assignment of human ARSA to chromosome 22. From study of human-rodent hybrid clones, {16:Geurts van Kessel et al. (1980)} concluded that arylsulfatase A is located distal to 22q13. In an infant with deletion of 22q13.31-qter, {42:Narahara et al. (1992)} found partial deficiency of ARSA, indicating that the ARSA locus was in the deleted region. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent In fibroblasts of 2 patients with metachromatic leukodystrophy (MLD; {250100}), {51:Stein et al. (1989)} detected ARSA RNA species of similar size. One was a form in which synthesis of ARSA polypeptides was not detectable, and the second was a form in which catalytically active enzyme was synthesized but was unstable in lysosomes. In patients with MLD, {46:Polten et al. (1991)}, {18:Gieselmann et al. (1991)}, {32:Kondo et al. (1991)}, {6:Bohne et al. (1991)}, and {14:Fluharty et al. (1991)} identified mutations in the ARSA gene (e.g., {607574.0003}). {20:Gieselmann et al. (1994)} stated that 31 amino acid substitutions, 1 nonsense mutation, 3 small deletions, 3 splice donor site mutations, and 1 combined missense/splice donor site mutation had been identified in the ARSA gene in metachromatic leukodystrophy. Two of these mutant alleles account for about 25% of MLD alleles each. {30:Kappler et al. (1994)} found that a patient with late infantile MLD was a genetic compound for 2 alleles, each of which carried 2 deleterious mutations. One allele carried 2 missense mutations; the other allele bore a splice donor site mutation and a missense mutation, both of which had previously been described but on different alleles. When ARSA cDNAs carrying these mutations, separately or in combination, were transfected into baby hamster kidney cells, expression of arylsulfatase A activity could not be detected. Among the lysosomal storage disorders, a single allele with 2 disease-causing mutations had been described for the GLA gene in Fabry disease ({301500.0011}) and in the complex glucocerebrosidase alleles associated with Gaucher disease ({230800.0009}). {2:Barth et al. (1995)} found 7 novel mutations in ARSA associated with MLD that they had detected by chemical mismatch analysis. {10:Coulter-Mackie et al. (1995)} described a child with MLD who had inherited a common splicing mutation, termed the 'I' allele, from the father and had a ring chromosome 22 from which the arylsulfatase A gene was deleted. {12:Draghia et al. (1997)} described 10 novel and 5 previously described mutations in 21 MLD patients (14 late infantile and 7 juvenile cases), confirming the heterogeneity of mutations causing MLD. One of the 10 novel mutations was an R496H missense change. {21:Gomez-Lira et al. (1998)} described mutations in the ARSA gene in 2 Italian patients with metachromatic leukodystrophy, one with juvenile onset and the other with adult onset. Both carried the ile179-to-ser mutation ({607574.0008}) in compound heterozygosity with distinct null mutations. The patient with juvenile onset also had a previously described splice site mutation, 459+1G-A ({607574.0003}), and the patient with adult onset had a previously undescribed mutation, pro135 to leu ({607574.0042}). Pseudoarylsulfatase A Deficiency Alleles {19:Gieselmann et al. (1989)} found that the pseudoarylsulfatase A deficiency ({250100}) allele had 2 A-to-G transitions: an asn350-to-ser mutation in exon 6, causing the loss of an N-glycosylation site ({607574.0002}), and the other occurring in exon 8 at the 3-prime end of the gene, causing the loss of a polyadenylation signal ({607574.0001}). {17:Gieselmann (1991)} found that these 2 mutations could be detected simultaneously with a rapid 3-prime-mismatch polymerase chain reaction. {50:Shen et al. (1993)} found another complication: a pseudodeficiency allele in which only 1 of the 2 A-to-G mutations was present. Although the ARSA pseudodeficiency allele contains 2 sequence alterations, a polyadenylation defect ({607574.0001}) and an amino acid substitution, N350S ({607574.0002}), the reduction in arylsulfatase activity had previously been attributed to the polyadenylation defect which reduces the amount of ARSA mRNA and hence arylsulfatase A protein by approximately 90%. {22:Harvey et al. (1998)} performed ribonuclease protection assay analysis of ARSA mRNA transcripts and investigated the activity and lysosomal localization of protein expressed by an ARSA expression construct containing the N350S variant. They concluded that both the N350S and the polyadenylation defect play roles in biochemically defining the pseudodeficiency phenotype. The combined effect of the reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein to the lysosome was estimated to reduce ARSA activity in the pseudodeficiency homozygote to approximately 8% of normal. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent In 34 individuals with low ASA activity, {29:Kappler et al. (1991)} identified 3 different classes: homozygosity for the pseudodeficiency allele (ASAp/ASAp) (10 individuals), compound heterozygosity for ASAp and ASA- (6 individuals), and homozygosity of ASA- (16 individuals). The genotypes exhibited different levels of residual ASA activity. ASAp/ASAp was associated with normal sulfatide degrading capacity and a reduced ASA activity that was the highest of the 3 classes (10-50% of normal). ASAp/ASAp subjects showed no evidence of MLD. ASAp/ASA- subjects showed mildly reduced sulfatide degrading capacity and a reduced ASA activity that was in between the other 2 classes (10% of controls). ASAp/ASA- subjects were either healthy or showed mild neurologic abnormalities. ASA-/ASA- subjects showed markedly reduced sulfatide degradation and markedly reduced ASA activity. Only the ASA-/ASA- genotype was associated with the development of both early- and late-onset MLD, including neuropsychiatric symptoms. {5:Berger et al. (1999)} described a family with 3 sibs, 1 of whom developed classic late infantile MLD, fatal at age 5 years, with deficient ARSA activity and increased galactosylsulfatide (GS) excretion. The other 2 sibs, apparently healthy at 12.5 and 15 years, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation analysis demonstrated that 3 different ARSA mutations accounted for the intrafamilial phenotypic heterogeneity. The late infantile patient inherited from his mother the frequent IVS2DS+1G-A mutation ({607574.0003}), and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG). The 2 clinically unaffected sibs carried the maternal mutation IVS2DS+1G-A and, on their paternal allele, a novel C-to-T transition at nucleotide 2435 in exon 8, resulting in an ala464-to-val amino acid substitution. The father's genotype thus was 7delG/A464V. The A464V mutation was not found in 18 unrelated MLD patients and 50 controls. A464V, although clearly modifying ARSA and GS levels, apparently has little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele ({607574.0001}). The results demonstrated that in certain genetic conditions the ARSA and GS values may not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally similar to A464V may exist which, together with 0-type mutations such as IVS2DS+1G-A, may cause ARSA and GS levels in the pathologic range but no clinical manifestation of the disease. {48:Regis et al. (2002)} identified a late infantile MLD patient carrying on one allele a novel E253K mutation ({607574.0044}) and the known T391S polymorphism, and on the other allele the common P426L mutation ({607574.0004}), usually associated with the adult or juvenile form of the disease, and the N350S ({607574.0002}) and *96A-G pseudodeficiency mutations. To analyze the contribution of mutations based on the same allele to enzyme activity reduction, as well as the possible phenotype implications, they performed transient expression experiments using ARSA cDNAs carrying the identified mutations separately or in combination. Their results indicated that mutants carrying multiple mutations cause greater reduction of ARSA activity than do the corresponding single mutants, the total deficiency likely corresponding to the sum of the reductions attributed to each mutation. Consequently, each mutation may contribute to the ARSA activity reduction and, therefore, to the degree of disease severity. This is particularly important for the alleles containing a disease-causing mutation and the pseudodeficiency mutations: in these alleles pseudodeficiency could play a role in affecting the clinical phenotype. {47:Rauschka et al. (2006)} evaluated 42 patients with late-onset MLD, 22 of whom were homozygous for the P426L mutation and 20 who were compound heterozygous for I179S ({607574.0008}) and another pathogenic ARSA mutation. Patients homozygous for the P426L mutation presented with progressive gait disturbance caused by spasticity paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at disease onset but became more apparent as the disease evolved. Peripheral nerve conduction velocities were decreased. In contrast, patients who were heterozygous for I179S presented with schizophrenia-like behavior changes, social dysfunction, and mental decline, but motor deficits were scarce. There was less residual ARSA activity in those with P426L mutations compared to those with I179S mutations. textSectionName genotypePhenotypeCorrelations textSectionTitle Population Genetics textSectionContent {49:Ricketts et al. (1998)} demonstrated that the ARSA polymorphism R496H has a relatively high frequency in an African American population, i.e., a frequency of 0.09 in 61 subjects tested. One normal 21-year-old subject was homozygous for the R496H mutation without evidence of MLD. The ARSA enzyme activity in subjects with or without R496H was found to be normal. textSectionName populationGenetics textSectionTitle Animal Model textSectionContent {41:Matzner et al. (2005)} treated Arsa-knockout mice by intravenous injection of recombinant human ARSA. Uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney, and very low into brain. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections of 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also reduced sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential suggested benefit of enzyme replacement therapy on nervous system function. textSectionName animalModel geneMapExists true editHistory carol : 03/13/2013 carol : 9/3/2009 wwang : 5/21/2008 terry : 5/19/2008 carol : 10/23/2007 wwang : 8/23/2007 ckniffin : 7/31/2007 terry : 11/16/2006 carol : 8/8/2003 carol : 8/1/2003 carol : 7/9/2003 carol : 7/9/2003 ckniffin : 6/24/2003 ckniffin : 6/24/2003 carol : 2/28/2003 ckniffin : 2/27/2003 ckniffin : 2/27/2003 dateCreated Mon, 24 Feb 2003 03:00:00 EST creationDate Cassandra L. Kniffin : 2/24/2003 epochUpdated 1363158000 dateUpdated Wed, 13 Mar 2013 03:00:00 EDT referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7906588 publisherName HighWire Press title Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients. mimNumber 607574 referenceNumber 1 publisherAbbreviation HighWire pubmedID 7906588 source Hum. Molec. Genet. 2: 2117-2121, 1993. authors Barth, M. L., Fensom, A., Harris, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Identification of seven novel mutations associated with metachromatic leukodystrophy. mimNumber 607574 referenceNumber 2 pubmedID 7581401 source Hum. Mutat. 6: 170-176, 1995. authors Barth, M. L., Fensom, A., Harris, A. pubmedImages false title Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. mimNumber 607574 referenceNumber 3 pubmedID 8095918 source Hum. Genet. 91: 73-77, 1993. authors Barth, M. L., Fensom, A., Harris, A. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7815433 publisherName HighWire Press title Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. mimNumber 607574 referenceNumber 4 publisherAbbreviation HighWire pubmedID 7815433 source J. Med. Genet. 31: 667-671, 1994. authors Barth, M. L., Ward, C., Harris, A., Saad, A., Fensom, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:1<61::AID-HUMU7>3.0.CO;2-H publisherName John Wiley & Sons, Inc. title Coincidence of two novel arylsulfatase A alleles and mutation 459+1G-A within a family with metachromatic leukodystrophy: molecular basis of phenotypic heterogeneity. mimNumber 607574 referenceNumber 5 publisherAbbreviation Wiley pubmedID 9888390 source Hum. Mutat. 13: 61-68, 1999. authors Berger, J., Gmach, M., Mayr, U., Molzer, B., Bernheimer, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy. mimNumber 607574 referenceNumber 6 pubmedID 1676699 source Hum. Genet. 87: 155-158, 1991. authors Bohne, W., von Figura, K., Gieselmann, V. pubmedImages false title Expression of human arylsulfatase A in man-hamster somatic cell hybrids. mimNumber 607574 referenceNumber 7 pubmedID 37046 source Cytogenet. Cell Genet. 22: 182-185, 1978. authors Bruns, G. A. P., Mintz, B. J., Leary, A. C., Regina, V. M., Gerald, P. S. pubmedImages false source ESGLD Workshop Delphi, and Greece, and Oct, 1993. mimNumber 607574 authors Caillaud, C., Blanchor, C., Akli, S., Crosnier, J. M., Puech, J. P., Kahn, A., Poenaru, L. title Molecular basis of late infantile metachromatic leukodystrophy in France. (Abstract) referenceNumber 8 title Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-to-A mutation and a newly identified missense mutation (thr408-to-ile) in a Spanish family. mimNumber 607574 referenceNumber 9 pubmedID 11456299 source Ann. Neurol. 50: 108-112, 2001. authors Comabella, M., Waye, J. S., Raguer, N., Eng, B., Dominguez, C., Navarro, C., Borras, C., Krivit, W., Montalban, X. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8558556 publisherName HighWire Press title Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22. mimNumber 607574 referenceNumber 10 publisherAbbreviation HighWire pubmedID 8558556 source J. Med. Genet. 32: 787-791, 1995. authors Coulter-Mackie, M. B., Rip, J., Ludman, M. D., Beis, J., Cole, D. E. C. pubmedImages false publisherUrl http://highwire.stanford.edu title Lysosomal arylsulfatase deficiencies in humans: chromosome assignment of arylsulfatase A and B. mimNumber 607574 referenceNumber 11 pubmedID 36611 source Proc. Nat. Acad. Sci. 76: 1957-1961, 1979. authors DeLuca, C., Brown, J. A., Shows, T. B. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7 publisherName John Wiley & Sons, Inc. title Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase gene. mimNumber 607574 referenceNumber 12 publisherAbbreviation Wiley pubmedID 9090526 source Hum. Mutat. 9: 234-242, 1997. authors Draghia, R., Letourneur, F., Drugan, C., Manicom, J., Blanchot, C., Kahn, A., Poenaru, L., Caillaud, C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11061266 publisherName HighWire Press title Adult-onset MLD: a gene mutation with isolated polyneuropathy. mimNumber 607574 referenceNumber 13 publisherAbbreviation HighWire pubmedID 11061266 source Neurology 55: 1036-1039, 2000. authors Felice, K. J., Gomez Lira, M., Natowicz, M., Grunnet, M. L., Tsongalis, G. J., Sima, A. A. F., Kaplan, R. F. pubmedImages false publisherUrl http://highwire.stanford.edu title Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient. mimNumber 607574 referenceNumber 14 pubmedID 1684088 source Am. J. Hum. Genet. 49: 1340-1350, 1991. authors Fluharty, A. L., Fluharty, C. B., Bohne, W., von Figura, K., Gieselmann, V. pubmedImages false title Conserved autosomal syntenic group on mouse (MMU) chromosome 15 and human (HSA) chromosome 22: assignment of a gene for arylsulfatase A to MMU 15 and regional mapping of DIA1, ARSA, and ACO2 on HSA22. mimNumber 607574 referenceNumber 15 pubmedID 6118238 source Cytogenet. Cell Genet. 31: 58-69, 1981. authors Francke, U., Tetri, P., Taggart, R. T., Oliver, N. pubmedImages false title Regional localization of the genes coding for human ACO2, ARSA, and NAGA on chromosome 22. mimNumber 607574 referenceNumber 16 pubmedID 7192199 source Cytogenet. Cell Genet. 28: 169-172, 1980. authors Geurts van Kessel, A. H. M., Westerveld, A., de Groot, P. G., Meera Khan, P., Hagemeijer, A. pubmedImages false title An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy. mimNumber 607574 referenceNumber 17 pubmedID 1671769 source Hum. Genet. 86: 251-255, 1991. authors Gieselmann, V. pubmedImages false title Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. mimNumber 607574 referenceNumber 18 pubmedID 1678251 source Am. J. Hum. Genet. 49: 407-413, 1991. authors Gieselmann, V., Fluharty, A. L., Tonnesen, T., Von Figura, K. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2574462 publisherName HighWire Press title Arylsulfatase A pseudodeficiency: loss of a polyadenylylation (sic) signal and N-glycosylation site. mimNumber 607574 referenceNumber 19 publisherAbbreviation HighWire pubmedID 2574462 source Proc. Nat. Acad. Sci. 86: 9436-9440, 1989. authors Gieselmann, V., Polten, A., Kreysing, J., von Figura, K. pubmedImages false publisherUrl http://highwire.stanford.edu title Molecular genetics of metachromatic leukodystrophy. mimNumber 607574 referenceNumber 20 pubmedID 7866401 source Hum. Mutat. 4: 233-242, 1994. authors Gieselmann, V., Zlotogora, J., Harris, A., Wenger, D. A., Morris, C. P. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/8102004/81020459.htm publisherName Springer title Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation. mimNumber 607574 referenceNumber 21 publisherAbbreviation Springer pubmedID 9600244 source Hum. Genet. 102: 459-463, 1998. Note: Erratum: Hum. Genet. 102: 602 only, 1998. authors Gomez-Lira, M., Perusi, C., Mottes, M., Pignatti, P. F., Manfredi, M., Rizzuto, N., Salviati, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9668161 publisherName HighWire Press title Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype. mimNumber 607574 referenceNumber 22 publisherAbbreviation HighWire pubmedID 9668161 source Hum. Molec. Genet. 7: 1215-1219, 1998. authors Harvey, J. S., Carey, W. F., Morris, C. P. pubmedImages false publisherUrl http://highwire.stanford.edu title An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy. mimNumber 607574 referenceNumber 23 pubmedID 8104633 source Hum. Mutat. 2: 261-267, 1993. authors Harvey, J. S., Nelson, P. V., Carey, W. F., Robertson, E. F., Morris, C. P. pubmedImages false title Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy. mimNumber 607574 referenceNumber 24 pubmedID 8101083 source DNA Cell Biol. 12: 493-498, 1993. authors Hasegawa, Y., Kawame, H., Eto, Y. pubmedImages false title Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing. mimNumber 607574 referenceNumber 25 pubmedID 7909527 source Hum. Genet. 93: 415-420, 1994. authors Hasegawa, Y., Kawame, H., Ida, H., Ohashi, T., Eto, Y. pubmedImages false title Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. mimNumber 607574 referenceNumber 26 pubmedID 7825603 source Am. J. Hum. Genet. 56: 51-57, 1995. authors Heinisch, U., Zlotogora, J., Kafert, S., Gieselmann, V. pubmedImages false title An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A. mimNumber 607574 referenceNumber 27 pubmedID 7902317 source Hum. Genet. 92: 451-456, 1993. authors Honke, K., Kobayashi, T., Fujii, T., Gasa, S., Xu, M., Takamaru, Y., Kondo, R., Tsuji, S., Makita, A. pubmedImages false title Confirmation of the assignment of the gene for arylsulfatase A to chromosome 22 using somatic cell hybrids. mimNumber 607574 referenceNumber 28 pubmedID 38202 source Hum. Genet. 49: 33-39, 1979. authors Hors-Cayla, M. C., Heuertz, S., Van Cong, N., Weil, D., Frezal, J. pubmedImages false title Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency. mimNumber 607574 referenceNumber 29 pubmedID 1673113 source Hum. Genet. 86: 463-470, 1991. authors Kappler, J., Leinekugel, P., Conzelmann, E., Kleijer, W. J., Kohlschutter, A., Tonnesen, T., Rochel, M., Freycon, F., Propping, P. pubmedImages false title Complex arylsulfatase A alleles causing metachromatic leukodystrophy. mimNumber 607574 referenceNumber 30 pubmedID 7981715 source Hum. Mutat. 4: 119-127, 1994. authors Kappler, J., Sommerlade, H. J., von Figura, K., Gieselmann, V. pubmedImages false title Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. mimNumber 607574 referenceNumber 31 pubmedID 1353340 source Ann. Neurol. 31: 256-261, 1992. authors Kappler, J., von Figura, K., Gieselmann, V. pubmedImages false title Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy. mimNumber 607574 referenceNumber 32 pubmedID 1673291 source Am. J. Hum. Genet. 48: 971-978, 1991. authors Kondo, R., Wakamatsu, N., Yoshino, H., Fukuhara, N., Miyatake, T., Tsuji, S. pubmedImages false title High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy. mimNumber 607574 referenceNumber 33 pubmedID 8101038 source Am. J. Hum. Genet. 53: 339-346, 1993. authors Kreysing, J., Bohne, W., Bosenberg, C., Marchesini, S., Turpin, J. C., Baumann, N., von Figura, K., Gieselmann, V. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2956&date=1990&volume=191&issue=3&spage=627 publisherName Blackwell Publishing title Structure of the arylsulfatase A gene. mimNumber 607574 referenceNumber 34 publisherAbbreviation Blackwell pubmedID 1975241 source Europ. J. Biochem. 191: 627-631, 1990. authors Kreysing, J., von Figura, K., Gieselmann, V. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Diagnosis of arylsulfatase A deficiency. mimNumber 607574 referenceNumber 35 pubmedID 1357970 source Am. J. Med. Genet. 43: 976-982, 1992. authors Li, Z. G., Waye, J. S., Chang, P. L. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2002&volume=61&issue=5&spage=389 publisherName Blackwell Publishing title High prevalence of I179S mutation in patients with late-onset metachromatic leukodystrophy. (Letter) mimNumber 607574 referenceNumber 36 publisherAbbreviation Blackwell pubmedID 12081727 source Clin. Genet. 61: 389-390, 2002. authors Lugowska, A., Berger, J., Tylki-Szymanska, A., Czartoryska, B., Loschl, B., Molzer, B. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1021/bi9714924 publisherName American Chemical Society title Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. mimNumber 607574 referenceNumber 37 publisherAbbreviation ACS pubmedID 9521684 source Biochemistry 37: 3654-3664, 1998. authors Lukatela, G., Krauss, N., Theis, K., Selmer, T., Gieselmann, V., von Figura, K., Saenger, W. pubmedImages false publisherUrl http://pubs.acs.org articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:4<337::AID-HUMU12>3.0.CO;2-F publisherName John Wiley & Sons, Inc. title Metachromatic leucodystrophy in Portugal--finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC. mimNumber 607574 referenceNumber 38 publisherAbbreviation Wiley pubmedID 10220151 source Hum. Mutat. 13: 337-338, 1999. authors Marcao, A., Amaral, O., Pinto, E., Pinto, R., Sa Miranda, M. C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X03009690 publisherName Elsevier Science title Oligomerization capacity of two arylsulfatase A mutants: C300F and P425T. mimNumber 607574 referenceNumber 39 publisherAbbreviation ES pubmedID 12788103 source Biochem. Biophys. Res. Commun. 306: 293-297, 2003. authors Marcao, A., Azevedo, J. E., Gieselmann, V., Sa Miranda, M. C. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.10822 publisherName John Wiley & Sons, Inc. title Biochemical characterization of two (C300F, P425T) arylsulfatase A missense mutations. mimNumber 607574 referenceNumber 40 publisherAbbreviation Wiley pubmedID 12503099 source Am. J. Med. Genet. 116A: 238-242, 2003. authors Marcao, A., Simonis, H., Schestag, F., Sa Miranda, M. C., Gieselmann, V. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15772092 publisherName HighWire Press title Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. mimNumber 607574 referenceNumber 41 publisherAbbreviation HighWire pubmedID 15772092 source Hum. Molec. Genet. 14: 1139-1152, 2005. authors Matzner, U., Herbst, E., Hedayati, K. K., Lullmann-Rauch, R., Wessig, C., Schroeder, S., Eistrup, C., Moeller, C., Fogh, J., Gieselmann, V. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1352356 publisherName HighWire Press title Terminal 22q deletion associated with a partial deficiency of arylsulphatase A. mimNumber 607574 referenceNumber 42 publisherAbbreviation HighWire pubmedID 1352356 source J. Med. Genet. 29: 432-433, 1992. authors Narahara, K., Takahashi, Y., Murakami, M., Tsuji, K., Yokoyama, Y., Murakami, R., Ninomiya, S., Seino, Y. pubmedImages false publisherUrl http://highwire.stanford.edu title Population frequency of the arylsulphatase A pseudo-deficiency allele. mimNumber 607574 referenceNumber 43 pubmedID 1674719 source Hum. Genet. 87: 87-88, 1991. authors Nelson, P. V., Carey, W. F., Morris, C. P. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/7101002/71010135.htm publisherName Springer title Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency. mimNumber 607574 referenceNumber 44 publisherAbbreviation Springer pubmedID 9402957 source Hum. Genet. 101: 135-140, 1997. authors Ott, R., Waye, J. S., Chang, P. L. pubmedImages false publisherUrl http://www.springeronline.com/ title Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene. mimNumber 607574 referenceNumber 45 pubmedID 7833949 source Hum. Mutat. 4: 199-207, 1994. authors Pastor-Soler, N. M., Rafi, M. A., Hoffman, J. D., Hu, D., Wenger, D. A. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199101033240104?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Molecular basis of different forms of metachromatic leukodystrophy. mimNumber 607574 referenceNumber 46 publisherAbbreviation ATYPON pubmedID 1670590 source New Eng. J. Med. 324: 18-22, 1991. authors Polten, A., Fluharty, A. L., Fluharty, C. B., Kappler, J., von Figura, K., Gieselmann, V. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16966551 publisherName HighWire Press title Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. mimNumber 607574 referenceNumber 47 publisherAbbreviation HighWire pubmedID 16966551 source Neurology 67: 859-863, 2006. authors Rauschka, H., Colsch, B., Baumann, N., Wevers, R., Schmidbauer, M., Krammer, M., Turpin, J.-C., Lefevre, M., Olivier, C., Tardieu, S., Krivit, W., Moser, H., {and 10 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1007/s00439-002-0701-y publisherName Springer title Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. mimNumber 607574 referenceNumber 48 publisherAbbreviation Springer pubmedID 11941485 source Hum. Genet. 110: 351-355, 2002. authors Regis, S., Corsolini, F., Stroppiano, M., Cusano, R., Filocamo, M. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1998)12:4<238::AID-HUMU3>3.0.CO;2-B publisherName John Wiley & Sons, Inc. title The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy. mimNumber 607574 referenceNumber 49 publisherAbbreviation Wiley pubmedID 9744473 source Hum. Mutat. 12: 238-239, 1998. authors Ricketts, M. H., Poretz, R. D., Manowitz, P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency. mimNumber 607574 referenceNumber 50 pubmedID 8456837 source Am. J. Med. Genet. 45: 631-637, 1993. authors Shen, N., Li, Z.-G., Waye, J. S., Francis, G., Chang, P. L. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2562955 publisherName HighWire Press title Cloning and expression of human arylsulfatase A. mimNumber 607574 referenceNumber 51 publisherAbbreviation HighWire pubmedID 2562955 source J. Biol. Chem. 264: 1252-1259, 1989. authors Stein, C., Gieselmann, V., Kreysing, J., Schmidt, B., Pohlmann, R., Waheed, A., Meyer, H. E., O'Brien, J. S., von Figura, K. pubmedImages false publisherUrl http://highwire.stanford.edu title Two allelic forms of human arylsulfatase A with different numbers of asparagine-linked oligosaccharides. mimNumber 607574 referenceNumber 52 pubmedID 6132551 source Am. J. Hum. Genet. 35: 228-233, 1983. authors Waheed, A., Steckel, F., Hasilik, A., von Figura, K. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0753-3322(94)90049-3 publisherName Elsevier Science title Late infantile metachromatic leukodystrophy in Israel. mimNumber 607574 referenceNumber 53 publisherAbbreviation ES pubmedID 7858169 source Biomed. Pharmacother. 48: 347-350, 1994. authors Zlotogora, J., Gieselman, V., von Figura, K., Zeigler, M., Bach, G. pubmedImages false publisherUrl http://www.elsevier.com/ seeAlso Bruns et al. (1978); Francke et al. (1981); Waheed et al. (1983)

entryList

entry status live allelicVariantExists true epochCreated 1016092800 geneMap geneSymbols MLYCD, MCD sequenceID 11330 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 606761 phenotypeInheritance Autosomal recessive phenotype Malonyl-CoA decarboxylase deficiency phenotypeMimNumber 248360 chromosomeLocationStart 83932719 chromosomeSort 547 chromosomeSymbol 16 mimNumber 606761 geneInheritance None confidence P mappingMethod R, Psh geneName Malonyl-CoA decarboxylase mouseMgiID MGI:1928485 mouseGeneSymbol Mlycd computedCytoLocation 16q23.3 cytoLocation 16q24 transcript uc002fgz.3 chromosomeLocationEnd 83962427 chromosome 16 contributors Marla J. F. O'Neill - updated : 2/17/2004 Victor A. McKusick - updated : 10/23/2003 clinicalSynopsisExists false mimNumber 606761 allelicVariantList allelicVariant status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY dbSnps rs104894528 text In a consanguineous Scottish patient with malonyl-CoA decarboxylase deficiency ({248360}) reported by {5:MacPhee et al. (1993)}, {3:FitzPatrick et al. (1999)} identified a C-to-G transversion at nucleotide 442 of the MLYCD gene, resulting in a ser148-to-ter substitution in the N-terminal half of the protein. mutations MLYCD, SER148TER number 1 clinvarAccessions RCV000004270;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY text In a consanguineous Scottish patient with malonyl-CoA decarboxylase deficiency ({248360}) reported by {5:MacPhee et al. (1993)}, {3:FitzPatrick et al. (1999)} identified an apparently homozygous A-to-G transition at position -14 in intron 4 of the MLYCD gene. The mutation created a novel 3-prime splice site within the intron, resulting in a 13-bp insertion in the mature RNA that caused a frameshift with predicted protein truncation. mutations MLYCD, IVS4AS, A-G, -14 number 2 clinvarAccessions RCV000004271;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY text In a patient with malonicaciduria, hypertrophic cardiomyopathy, and renal dysplasia as well as micropenis and hypotonia ({248360}), {4:Gao et al. (1999)} identified a 4-bp deletion at the 3-prime end of exon 2 of the malonyl-CoA decarboxylase cDNA. The deletion of GTGA beginning at nucleotide 638 was found in homozygosity in this patient; both of his parents were carriers. mutations MLYCD, 4-BP DEL, 638GTGA number 3 clinvarAccessions RCV000004272;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY text In a patient with severe malonyl-CoA decarboxylase deficiency ({248360}), {7:Sacksteder et al. (1999)} identified a deletion of 2 T residues at nucleotides 947 and 948 of the MLYCD cDNA. A second mutation was not identified. mutations MLYCD, 2-BP DEL, 947TT number 4 clinvarAccessions RCV000004273;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY dbSnps rs121908081 text In a patient reported by {2:Brown et al. (1984)} with MLYCD deficiency ({248360}), {8:Wightman et al. (2003)} found a G-to-A transition at nucleotide 8 of the cDNA predicted to result in a gly3-to-asp (G3D) protein change; the mutation was present in homozygous state. The MLYCD protein was mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a 4-amino acid conserved N-terminal motif. mutations MLYCD, GLY3ASP number 5 clinvarAccessions RCV000004274;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY dbSnps rs28937908 text In a patient reported by {6:Matalon et al. (1993)} with MLYCD deficiency ({248360}), {8:Wightman et al. (2003)} found homozygosity for a 119T-C transition in homozygous form predicted to result in an met40-to-thr (M40T) missense mutation in the protein. Immunocytochemistry in the patient's cells showed MLYCD to be localized to the perinuclear region of the cells. The fact that the patient had 25% enzyme activity but had a severe phenotype with cardiomyopathy showed that normal processing and targeting is necessary for MLYCD function (as outlined by {8:Wightman et al. (2003)}), other interpretations of the nature of the mutation in this case had been suggested by other workers. mutations MLYCD, MET40THR number 6 clinvarAccessions RCV000004275;;1 status live name MALONYL-CoA DECARBOXYLASE DEFICIENCY text In a patient reported by {9:Yano et al. (1997)} with MLYCD deficiency ({248360}), {8:Wightman et al. (2003)} identified a 25-bp deletion (84-108del) in homozygous state. The deletion was located between the putative mitochondrial and peroxisomal initiating codons (M1 and M40). The protein on immunohistochemical study showed punctate perinuclear staining, as in the case of the M40T mutation ({606761.0006}), which also showed ablation of the M40 peroxisomal initiating codon. mutations MLYCD, 25-BP DEL, NT84 number 7 clinvarAccessions RCV000004276;;1 prefix * titles alternativeTitles MCD preferredTitle MALONYL-CoA DECARBOXYLASE; MLYCD textSectionList textSection textSectionTitle Description textSectionContent Malonyl-CoA decarboxylase ({EC 4.1.1.9}) catalyzes the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide. It is thought to be involved in aspects of fatty acid biosynthesis and oxidation ({7:Sacksteder et al., 1999}). textSectionName description textSectionTitle Cloning textSectionContent Malonyl-CoA decarboxylase is found most often in the liver, brain, heart, and skeletal muscle ({7:Sacksteder et al., 1999}). {4:Gao et al. (1999)} searched expressed sequence tag databases to identify human cDNAs with homology to the goose malonyl-CoA decarboxylase cDNA sequence. The 1,479-nucleotide human cDNA sequence is 70% identical to that of goose. {3:FitzPatrick et al. (1999)} identified a 2.1-kb human MCD cDNA encoding a 454-amino acid protein that shows 70.3% amino acid identity to goose Mcd. They found that the peptide sequence of the MCD enzyme contains a C-terminal peroxisomal targeting sequence (ser-lys-leu). This targeting sequence appeared to be functional in vivo, since the distribution of MCD enzymatic activity in rat liver homogenates, as measured by means of subcellular fractionation, strongly suggested that MCD was localized to peroxisomes in addition to mitochondria. To identify the human malonyl-CoA decarboxylase gene, {7:Sacksteder et al. (1999)} searched expressed sequence tag databases for sequences similar to that of goose malonyl-CoA decarboxylase, which contains the consensus sequence for the type 1 peroxisomal targeting signal (PTS1). textSectionName cloning textSectionTitle Gene Structure textSectionContent {4:Gao et al. (1999)} found that the intron/exon boundaries of the MLYCD gene are completely conserved in goose and human. textSectionName geneStructure textSectionTitle Mapping textSectionContent By radiation hybrid analysis, {7:Sacksteder et al. (1999)} mapped the MLYCD gene to 16q23-q24, between markers D16S422 and D16S402. Using mouse/human hybrid cell lines, {4:Gao et al. (1999)} mapped the malonyl-CoA decarboxylase gene to chromosome 16q24, in a 450-kb interval between D16S402 and D16S422. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {4:Gao et al. (1999)} identified a 4-bp deletion at the 3-prime end of exon 2 of the MLYCD gene ({606761.0003}) in homozygosity in a patient with malonyl-CoA decarboxylase deficiency ({248360}). By RT-PCR analysis of fibroblast RNA from 2 consanguineous Scottish patients with MCD deficiency reported by {5:MacPhee et al. (1993)}, {3:FitzPatrick et al. (1999)} identified homozygous mutations in the MCD gene ({606761.0002}-{606761.0003}). {7:Sacksteder et al. (1999)} identified a 2-bp deletion ({606761.0004}) in a patient with severe malonicaciduria. By genomic sequencing of the MLYCD gene, {8:Wightman et al. (2003)} succeeded in identifying 16 of 18 pathogenic alleles in 9 unrelated patients with malonyl-CoA decarboxylase deficiency. Fibroblast cell lines were available from 8 of these patients and 2 previously reported patients with homozygous MLYCD mutations. Western blot analysis using antisera raised to a C-terminal peptide detected a 66-kD band that was absent in 6 patients and substantially reduced in 3 patients. One patient showed an increase in protein levels with a prominent 'smeary' 68- to 183-kD band. Immunocytochemical analysis of MLYCD-expressing patient cell lines showed apparent intracellular mislocalization. An extreme N-terminal mutation, gly3 to asp ({606761.0005}), mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a 4-amino acid conserved N-terminal motif. Both a 25-base deletion (84-108del; {606761.0007}) between the putative mitochondrial and peroxisomal initiating codons (M1 and M40) and a point mutation ablating the second of these (met40 to thr; {606761.0006}) showed punctate perinuclear staining. As none of the 3 mislocalizing mutations were predicted to alter the catalytic function of the peptide, it seemed likely that correct subcellular localization of MLYCD is critical for its normal functioning. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {1:An et al. (2004)} showed that in rats fed a high-fat diet, whole-animal, muscle, and liver insulin resistance was ameliorated following hepatic overexpression of MCD, which decreased circulating free fatty acid (FFA) levels and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA, 2 candidate mediators of insulin resistance, were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. {1:An et al. (2004)} hypothesized that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity. textSectionName animalModel geneMapExists true editHistory wwang : 02/24/2010 terry : 2/22/2010 ckniffin : 12/30/2009 carol : 3/9/2005 alopez : 3/5/2004 carol : 2/17/2004 carol : 2/17/2004 cwells : 10/24/2003 terry : 10/23/2003 carol : 3/26/2002 ckniffin : 3/20/2002 dateCreated Thu, 14 Mar 2002 03:00:00 EST creationDate Cassandra L. Kniffin : 3/14/2002 epochUpdated 1266998400 dateUpdated Wed, 24 Feb 2010 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1038/nm995 publisherName Nature Publishing Group title Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. mimNumber 606761 referenceNumber 1 publisherAbbreviation NPG pubmedID 14770177 source Nature Med. 10: 268-274, 2004. authors An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., Newgard, C. B. pubmedImages false publisherUrl http://www.nature.com title Malonyl coenzyme A decarboxylase deficiency. mimNumber 606761 referenceNumber 2 pubmedID 6145813 source J. Inherit. Metab. Dis. 7: 21-26, 1984. authors Brown, G. K., Scholem, R. D., Bankier, A., Danks, D. M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62048-5 publisherName Elsevier Science title The molecular basis of malonyl-CoA decarboxylase deficiency. mimNumber 606761 referenceNumber 3 publisherAbbreviation ES pubmedID 10417274 source Am. J. Hum. Genet. 65: 318-326, 1999. authors FitzPatrick, D. R., Hill, A., Tolmie, J. L., Thorburn, D. R., Christodoulou, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jlr.org/cgi/pmidlookup?view=long&pmid=9869665 publisherName HighWire Press title Cloning and mutational analysis of human malonyl-coenzyme A decarboxylase. mimNumber 606761 referenceNumber 4 publisherAbbreviation HighWire pubmedID 9869665 source J. Lipid Res. 40: 178-182, 1999. authors Gao, J., Waber, L., Bennett, M. J., Gibson, K. M., Cohen, J. C. pubmedImages false publisherUrl http://highwire.stanford.edu title Malonyl coenzyme A decarboxylase deficiency. mimNumber 606761 referenceNumber 5 pubmedID 8259873 source Arch. Dis. Child. 69: 433-436, 1993. authors MacPhee, G. B., Logan, R. W., Mitchell, J. S., Howells, D. W., Tsotsis, E., Thorburn, D. R. pubmedImages false title Malonic aciduria and cardiomyopathy. mimNumber 606761 referenceNumber 6 pubmedID 7609455 source J. Inherit. Metab. Dis. 16: 571-573, 1993. authors Matalon, R., Michaels, K., Kaul, R., Whitman, V., Rodriguez-Novo, J., Goodman, S., Thorburn, D. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10455107 publisherName HighWire Press title MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency. mimNumber 606761 referenceNumber 7 publisherAbbreviation HighWire pubmedID 10455107 source J. Biol. Chem. 274: 24461-24468, 1999. authors Sacksteder, K. A., Morrell, J. C., Wanders, R. J. A., Matalon, R., Gould, S. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10264 publisherName John Wiley & Sons, Inc. title MLYCD mutation analysis: evidence for protein mistargeting as a cause of MLYCD deficiency. mimNumber 606761 referenceNumber 8 publisherAbbreviation Wiley pubmedID 12955715 source Hum. Mutat. 22: 288-300, 2003. authors Wightman, P. J., Santer, R., Ribes, A., Dougherty, F., McGill, N., Thorburn, D. R., FitzPatrick, D. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://link.springer.de/link/service/journals/00431/bibs/7156005/71560382.htm publisherName Springer title A new case of malonyl coenzyme A decarboxylase deficiency presenting with cardiomyopathy. mimNumber 606761 referenceNumber 9 publisherAbbreviation Springer pubmedID 9177981 source Europ. J. Pediat. 156: 382-383, 1997. authors Yano, S., Sweetman, L., Thorburn, D. R., Mofidi, S., Williams, J. C. pubmedImages false publisherUrl http://www.springeronline.com/ externalLinks mgiIDs MGI:1928485 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 530423741,110349749 refSeqAccessionIDs NG_009079.1 dermAtlas false hprdIDs 05999 swissProtIDs O95822 zfinIDs ZDB-GENE-070410-120 uniGenes Hs.644610 gtr true cmgGene false umlsIDs C1417196 genbankNucleotideSequences 4960187,30962891,148175232,21753086,12653044,38490540,74230027,148175231,5732236,5231268,511792812 geneTests true approvedGeneSymbols MLYCD geneIDs 23417 proteinSequences 12653045,30962892,110349750,4960188,5732237,5231269,8928067,119615919 geneticsHomeReferenceIDs gene;;MLYCD;;MLYCD locusSpecificDBs http://mlycd.hgu.mrc.ac.uk/;;MLYCD Allelic Variant Database

entryList

entry status live allelicVariantExists true epochCreated 726393600 geneMap geneSymbols MYO7A, USH1B, DFNB2, DFNA11 sequenceID 8479 phenotypeMapList phenotypeMap phenotypeMimNumber 601317 mimNumber 276903 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 124900 phenotypeMappingKey 3 phenotype Deafness, autosomal dominant 11 phenotypeMimNumber 600060 mimNumber 276903 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 220290 phenotypeMappingKey 3 phenotype Deafness, autosomal recessive 2 phenotypeMimNumber 276900 mimNumber 276903 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 276900 phenotypeMappingKey 3 phenotype Usher syndrome, type 1B chromosomeLocationStart 76839301 chromosomeSort 653 chromosomeSymbol 11 mimNumber 276903 geneInheritance None confidence C mappingMethod Fd geneName Myosin VIIA mouseMgiID MGI:104510 mouseGeneSymbol Myo7a computedCytoLocation 11q13.5 cytoLocation 11q13.5 transcript uc001oyb.2 chromosomeLocationEnd 76926285 chromosome 11 contributors Marla J. F. O'Neill - updated : 11/2/2012 Patricia A. Hartz - updated : 5/2/2012 Cassandra L. Kniffin - updated : 12/21/2011 Ada Hamosh - updated : 5/6/2011 Marla J. F. O'Neill - updated : 5/3/2011 Cassandra L. Kniffin - updated : 2/14/2011 Cassandra L. Kniffin - reorganized : 10/24/2008 Cassandra L. Kniffin - updated : 10/22/2008 George E. Tiller - updated : 1/31/2006 Victor A. McKusick - updated : 3/31/2005 Victor A. McKusick - updated : 7/14/2004 Victor A. McKusick - updated : 6/25/2003 Patricia A. Hartz - updated : 3/10/2003 George E. Tiller - updated : 12/17/2001 George E. Tiller - updated : 11/17/2000 Victor A. McKusick - updated : 6/30/1999 Victor A. McKusick - updated : 3/1/1999 Victor A. McKusick - updated : 2/19/1999 Victor A. McKusick - updated : 5/27/1998 Rebekah S. Rasooly - updated : 3/9/1998 Victor A. McKusick - updated : 10/27/1997 Victor A. McKusick - updated : 10/17/1997 Victor A. McKusick - updated : 6/2/1997 Victor A. McKusick - updated : 2/28/1997 Moyra Smith - updated : 9/6/1996 clinicalSynopsisExists false mimNumber 276903 allelicVariantList allelicVariant status live name USHER SYNDROME, TYPE IB dbSnps rs121965079 text In affected members of a family with Usher syndrome type IB ({276900}), {31:Weil et al. (1995)} identified compound heterozygosity for 2 mutations in the MYO7A gene: a 163C-T transition in exon 1 resulting in an arg150-to-ter (R150X) substitution, and a 6-bp deletion ({276903.0003}). The R150X protein was predicted to be truncated before the ATP-binding site. mutations MYO7A, ARG150TER number 1 clinvarAccessions RCV000012621;;1;;;RCV000036148;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs41298133 text In affected members of a family with Usher syndrome IB ({276900}), {31:Weil et al. (1995)} identified a heterozygous C-to-T transition in exon 3 of the MYO7A gene, resulting in a gln234-to-ter (Q234X) substitution and truncation of the protein before the actin-binding site. mutations MYO7A, GLN234TER number 2 clinvarAccessions RCV000036246;;1;;;RCV000012622;;1 status live name USHER SYNDROME, TYPE IB text In affected members of 2 unrelated families with Usher syndrome type IB ({276900}), {31:Weil et al. (1995)} identified the same in-frame 6-bp deletion (GACACT) in exon 3 of the MYO7A gene at codon 217, leading to loss of amino acid residues asp (D) and ile (I). In 1 family, the 2 affected brothers inherited the deleted allele from their father and a nonsense mutation ({276903.0001}) from their mother. The 2 families originated from different geographic regions, suggesting that 2 independent mutational events were responsible for the 6-bp deletion. The deletion occurred in an 11-bp sequence containing 2 5-bp direct repeats, and it was considered possible that either replication slippage or slipped-strand mispairing was responsible for the mutational event. mutations MYO7A, 6-BP DEL, EX3 number 3 clinvarAccessions RCV000012623;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs28934610 text In individuals with Usher syndrome type IB ({276900}), {31:Weil et al. (1995)} identified a G-to-A transition in the MYO7A gene, resulting in an arg212-to-his (R212H) substitution. In another family, a C-to-T transition resulted in an arg212-to-cys (R212C; {276903.0005}) substitution in the same codon. Both mutations were in exon 7 of the MYO7A gene. {34:Weston et al. (1996)} found that 8 of 23 mutant alleles detected in their study of Usher syndrome type IB were either R212H or R212C. In some instances, the R212H mutation was in cis with an R302H ({276903.0006}) mutation in exon 9. Affected sibs in a Dutch family were homozygous for the double mutation at both codons, while the affected sibs in a Finnish family showed only paternal inheritance of both mutations. Both R302H and R212H have been observed singly in affected persons; neither has been observed in controls, either singly or as double mutations. Although these 3 mutations were the most common ones observed, comprising approximately 50% of all mutations found, they still represented less than 3% of the total USH1B chromosomes studied. Furthermore, no linkage disequilibrium between USH1B and several adjacent polymorphic markers was found, suggesting that there are several independently occurring mutations rather than a common USH1B allele. mutations MYO7A, ARG212HIS number 4 clinvarAccessions RCV000036232;;1;;;RCV000012624;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs121965080 text See {276903.0004}, {31:Weil et al. (1995)}, and {34:Weston et al. (1996)}. mutations MYO7A, ARG212CYS number 5 clinvarAccessions RCV000012625;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs41298135 text See {276903.0004} and {34:Weston et al. (1996)}. mutations MYO7A, ARG302HIS number 6 clinvarAccessions RCV000036251;;1;;;RCV000012626;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 dbSnps rs121965081 text {24:Liu et al. (1997)} found mutations in the MYO7A gene in 2 of 8 families with autosomal recessive nonsyndromic deafness ({600060}) from the Sichuan province of China. In 1 family, 3 affected sibs were homozygous for an arg244-to-pro (R244P) substitution. {28:Riazuddin et al. (2008)} stated that the R244P mutation is located in the motor domain of the protein. In vitro studies with the mouse ortholog, R233P, showed that the mutant protein did not localize within stereocilia of hair cells, similar to that observed with MYO7A constructs corresponding to Usher syndrome IB ({276900}) mutants. Although R233P showed normal affinity to actin filaments, the ATPase rate was decreased compared to wildtype. mutations MYO7A, ARG244PRO number 7 clinvarAccessions RCV000012627;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 text In a Chinese family with nonsyndromic autosomal recessive deafness ({600060}), {24:Liu et al. (1997)} found that 2 sibs were compound heterozygotes for an acceptor splice site mutation of intron 3 (-2a-to-g) in 1 allele, while the other allele carried a T insertion in exon 28 ({276903.0009}), val1199insT(FS), leading to a frameshift and stop codon 28 amino acids downstream. mutations MYO7A, IVS3AS, A-G, -2 number 8 clinvarAccessions RCV000012628;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 text See {276903.0008} and {24:Liu et al. (1997)}. mutations MYO7A, 1-BP INS, EX28 number 9 clinvarAccessions RCV000012629;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 dbSnps rs121965082 text In affected members of a large consanguineous family from Tunisia in which 22 members were originally reported to have autosomal recessive sensorineural deafness ({600060}) ({16:Guilford et al., 1994}), {32:Weil et al. (1997)} identified a homozygous G-to-A transition at the last nucleotide of exon 15 in the MYO7A gene, resulting in a met599-to-ile (M599I) substitution. The mutation was not detected in 100 unaffected individuals living in the same Tunisian region who were not related to the affected family. {6:Ben Zina et al. (2001)} reevaluated the family reported by {16:Guilford et al. (1994)} and {32:Weil et al. (1997)}. Since the original reports, 5 patients had developed mild retinal degeneration in addition to the progressive deafness. Fundus examination of 1 patient showed spicule pigmentary changes consistent with retinal dystrophy. Another previously unaffected family member, homozygous for the mutation, had retinitis pigmentosa. Seven patients had abnormal vestibular function as assessed by caloric tests. {6:Ben Zina et al. (2001)} concluded that some patients in this Tunisian family had features consistent with Usher syndrome type IB ({276000}). The findings suggested that other factors must modulate the expression of the phenotype. mutations MYO7A, MET599ILE number 10 alternativeNames USHER SYNDROME, TYPE IB, INCLUDED clinvarAccessions RCV000012631;;1;;;RCV000012630;;1 status live name DEAFNESS, AUTOSOMAL DOMINANT 11 text In a Japanese family with autosomal dominant nonsyndromic hearing loss mapping to 11q (DFNA11; {601317}), {25:Liu et al. (1997)} demonstrated an in-frame 9-bp deletion in exon 22 of the MYO7A gene, leading to deletion of 3 amino acids (ala886-lys887-lys888) in the coiled-coil region of the protein. All affected members of the family had postlingual bilateral sensorineural hearing loss with subsequent gradual progression. This was the first mutation identified in the coiled-coiled region, which is thought to be responsible for dimerization of the molecule. {25:Liu et al. (1997)} postulated that the mutant protein interacted with the wildtype protein, resulting in a dominant-negative effect. mutations MYO7A, 9-BP DEL, EX22 number 11 clinvarAccessions RCV000012632;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs121965083 text {11:Cuevas et al. (1998)} studied a Spanish family with 3 members affected with Usher syndrome type IB ({276900}). Search for mutations in the MYO7A gene showed a cys628-to-ter (C682X) mutation in exon 16 segregating with the disorder in a homozygous state. mutations MYO7A, CYS628TER number 12 clinvarAccessions RCV000012633;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs35689081 text In 9 of 12 mutant alleles in 6 patients from Denmark with Usher syndrome type IB ({276900}), {18:Janecke et al. (1999)} identified a C-to-A transversion in exon 3 of the MYO7A gene, resulting in a cys31-to-ter (C31X) substitution. Although the families were not known to be related, genotyping for 6 intragenic polymorphisms suggested that the 9 mutation-bearing chromosomes originated from the same ancestor. {34:Weston et al. (1996)} had detected the same C31X mutation in a proband from Sweden and in a proband of Scandinavian ancestry from the United States. mutations MYO7A, CYS31TER number 13 clinvarAccessions RCV000012634;;1 status live name VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs375050157 text This variant is classified as a variant of unknown significance because its contribution to Usher syndrome has not been confirmed. {1:Adato et al. (1999)} suggested that digenic inheritance might be operative in a Yemenite family in which 2 of 8 children had Usher syndrome. Two affected brothers in this family had different Usher syndrome phenotypes. One had a typical USH1 phenotype ({276900}): he had a history of prelingual profound auditory impairment; he used sign language for communication, since hearing aids were unhelpful in his case; and developmental milestones in his childhood were consistent with congenital vestibular dysfunction. The other affected brother had a typical USH3 phenotype ({276902}): he had progressive hearing loss, with postlingual onset; he used hearing aids and verbal communication; and he received psychiatric therapy for mental problems. Both brothers had bilateral progressive pigmentary retinopathy, with onset during early adolescence. In both affected brothers, {1:Adato et al. (1999)} found homozygosity for a haplotype consistent with a location on chromosome 3, where the USH3 gene is located. Since one of the affected brothers had a USH1 phenotype, family members were screened for mutations in the MYO7A gene. On 1 maternal chromosome, transmitted to the brother with the USH1 phenotype and to 2 unaffected sibs, but not to the brother with the USH3 phenotype, they found a double mutation: a T-to-C transition in exon 25 of the MYO7A gene, predicted to cause a leu1087-to-pro (L1087P) substitution; and a guanine deletion 5 nucleotides upstream of this transition, predicted to cause a frameshift of the reading frame starting at codon 1089. This frameshift would result in the formation of a UGA stop codon 18 amino acids downstream from the deletion site and, therefore, in the translation of a truncated protein that lacked more than 50% of its normal amino acid sequence, which comprises most of the MYO7A tail domain. Segregation of the mutated MYO7A with healthy family members as well as with the more severe USH phenotype suggested a possible biologic interaction between MYO7A and the USH3 gene products. The mutated MYO7A appeared to be phenotypically expressed only on the background of 2 USH3 alleles. {2:Adato et al. (2002)} restudied the Jewish Yemenite family previously reported by {1:Adato et al. (1999)} and identified homozygosity for a 23-bp deletion in the CLRN1 gene ({606397.0007}) in the affected brothers. The authors stated that this represented a departure from the monogenic model for Usher syndrome. mutations MYO7A, 1-BP DEL AND LEU1087PRO number 14 clinvarAccessions RCV000012637;;1 status live name DEAFNESS, AUTOSOMAL DOMINANT 11 dbSnps rs121965084 text In affected members of a Dutch family with autosomal dominant nonsyndromic sensorineural deafness ({601317}), {26:Luijendijk et al. (2004)} identified a heterozygous 1373A-T transversion in exon 13 of the MYO7A gene, resulting in an asn458-to-ile (N458I) substitution. In a molecular model, the mutant protein was predicted to disrupt ATP binding and impair the myosin power stroke. mutations MYO7A, ASN458ILE number 15 clinvarAccessions RCV000012638;;1 status live name USHER SYNDROME, TYPE IB dbSnps rs121965085 text Through a systematic mutation screening of the genes known to cause type I Usher syndrome ({276900}) in patients from the U.S. and U.K., {27:Ouyang et al. (2005)} identified a 1996C-T transition in exon 17 of the MYO7A gene, resulting in an arg666-to-ter nonsense mutation (R666X). The mutation was predicted to truncate myosin VIIA by approximately 90%. Of the 12 mutations detected by {27:Ouyang et al. (2005)} at the MYO7A locus in patients with type I Usher syndrome, 5 of 21 alleles (23.8%) were R666X. A G-C transversion within the splice acceptor site of intron 27 ({276903.0017}) accounted for 3 of 21 alleles (14.3%). mutations MYO7A, ARG666TER number 16 clinvarAccessions RCV000012635;;1 status live name USHER SYNDROME, TYPE IB text See {276903.0016} and {27:Ouyang et al. (2005)}. mutations MYO7A, IVS27AS, G-C, -1 number 17 clinvarAccessions RCV000012636;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 text In affected members of a consanguineous Pakistani family with DFNB2 ({600060}), {28:Riazuddin et al. (2008)} identified a homozygous 3-bp deletion (5146delGAG) in exon 37 of the MYO7A gene, resulting in an in-frame loss of a conserved glutamate residue at codon 1716. This residue is located in the tail region between the SH3 domain and the second MyTH4 domain. In vitro studies targeting the homologous mutant 5146delGAG protein in cultured mouse cells indicated that the protein localized along the length of inner ear hair cell stereocilia similar to the wildtype protein. Similar studies with truncating MYO7A mutations resulting in Usher syndrome IB ({276900}) showed no localization to stereocilia. {28:Riazuddin et al. (2008)} concluded that the mutation in this family caused a less severe phenotype compared to that of Usher syndrome IB because of residual protein function. mutations MYO7A, 3-BP DEL, 5146GAG number 18 clinvarAccessions RCV000012639;;1 status live name DEAFNESS, AUTOSOMAL DOMINANT 11 dbSnps rs201539845 text In affected members of a Chinese family with autosomal dominant nonsyndromic deafness-11 ({601317}), {29:Sun et al. (2011)} identified a heterozygous 652G-A transition in exon 7 of the MYO7A gene, resulting in an asp218-to-asn (D218N) substitution in a conserved residue in the motor domain. The mutation was not found in 100 controls. Affected individuals had onset between ages 20 and 47 years of bilateral mild to severe symmetric hearing impairment particularly involving high frequencies. The audiogram was flat or downward sloping. Tinnitus occurred before hearing loss, but there was no vestibular involvement. mutations MYO7A, ASP218ASN number 19 clinvarAccessions RCV000022815;;1 status live name DEAFNESS, AUTOSOMAL DOMINANT 11 dbSnps rs387906699 text In affected members of a Chinese family with autosomal dominant nonsyndromic deafness-11 ({601317}), {29:Sun et al. (2011)} identified a heterozygous 2011G-A transition in exon 17 of the MYO7A gene, resulting in a gly671-to-ser (G671S) substitution in a conserved residue in the region of the myosin head converter domain. Affected individuals had onset between ages 10 and 39 years of bilateral mild to severe symmetric hearing loss affecting mainly low frequencies. The audiogram was flat or ascending. Tinnitus occurred before hearing loss, but there was no vestibular involvement. Electrocochleography in this family showed no evidence of endolymphatic hydrops. Molecular modeling suggested that the substituted serine side chain projects into a conserved hydrophobic pocket in the converter domain and relay loop of this region, generating steric hindrance with neighboring amino acid tyr477. mutations MYO7A, GLY671SER number 20 clinvarAccessions RCV000022816;;1 status live name DEAFNESS, AUTOSOMAL RECESSIVE 2 dbSnps rs387906700 text In 3 sibs, born of consanguineous Iranian parents, with autosomal recessive deafness-2 ({600060}), {17:Hildebrand et al. (2010)} identified a homozygous 1184G-A transition in exon 11 of the MYO7A gene, resulting in an arg395-to-his (R395H) substitution in a highly conserved residue in the motor domain of the protein. The mutation was not found in 94 Iranian control chromosomes or in 258 control chromosomes. Onset of hearing loss occurred between ages 7 months and 7 years. Audiologic testing revealed hearing loss at all frequencies, although low frequency hearing was less impaired. All had normal vestibular function, and funduscopic examination and visual acuity tests excluded retinitis pigmentosa in all patients at ages 39, 31, and 42 years, respectively. One patient had a milder phenotype, with later onset and less severe impairment, suggesting the presence of a genetic modifier. The findings confirmed that nonsyndromic hearing loss can be caused by mutation in the MYO7A gene. mutations MYO7A, ARG395HIS number 21 clinvarAccessions RCV000022817;;1 prefix * titles alternativeTitles MYOSIN, UNCONVENTIONAL, FAMILY VII, MEMBER A; MYU7A preferredTitle MYOSIN VIIA; MYO7A textSectionList textSection textSectionTitle Description textSectionContent The MYO7A gene encodes a protein classified as an unconventional myosin. Unconventional myosins are motor molecules with structurally conserved heads that move along actin filaments. Their highly divergent tails are presumed to be tethered to different macromolecular structures that move relative to actin filaments, thus enabling them to transport cargo ({31:Weil et al., 1995}). textSectionName description textSectionTitle Cloning textSectionContent By positional cloning, {31:Weil et al. (1995)} identified the MYO7A gene within the candidate gene region for Usher syndrome type IB (USH1B; see {276900}) on chromosome 11q. Clones corresponding to the gene were isolated from a retinal cDNA library. The deduced protein encoded most of the motor head of myosin and was 95% identical to the mouse protein. RT-PCR products were detected in human kidney, liver, and retina, but not in brain or lymphocytes transformed by Epstein-Barr virus. {33:Weil et al. (1996)} presented the cDNA sequence of myosin VIIA which predicted a 2,215-amino acid protein with a typical unconventional myosin structure. The protein was expected to dimerize into a 2-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily (see {130500}). Several alternatively spliced isoforms were identified. In situ hybridization analysis in human embryos demonstrated MYO7A expression in the retinal pigment epithelium and photoreceptor cells, as well as in cochlear and vestibular neuroepithelia. {15:Gibson et al. (1995)} identified the mouse Myo7a gene as being causative for the shaker-1 (sh1) phenotype, which is characterized by cochlear and vestibular dysfunction, but no retinal abnormalities. The authors identified the gene using positional cloning based on the fact that the olfactory marker protein gene (Omp) is very tightly linked to the mouse sh1 mutation on mouse chromosome 7. Among the 9 unique exon-trap products found in a YAC from this region, there was 1 that was used to isolate a 4.6-kb clone from a mouse inner-ear cDNA library. Sequence analysis demonstrated that this was the gene encoding myosin VIIA. The findings of both {31:Weil et al. (1995)} and {15:Gibson et al. (1995)} indicated that USH1B and 'shaker' are primary cytoskeletal protein defects. {10:Chen et al. (1996)} cloned cDNAs encoding a previously unexplored portion of the MYO7A gene. Two transcripts were found, one encoding the predicted 250-kD protein and another encoding a shorter form. Both transcripts were found in highest abundance in testis, although the shorter one was much less abundant. Both were detected in lymphocytes by RT-PCR. The myosin tail encoded by the long transcript includes a long repeat of approximately 460 amino acids. Each repeat contains a novel 'MyTH4' domain similar to domains in 3 other myosins, and a domain similar to the membrane-associated portion of talin ({186745}) and other members of the band 4.1 family. {20:Kelley et al. (1997)} found that the largest mRNA transcript is 7.4 kb. textSectionName cloning textSectionTitle Gene Structure textSectionContent {33:Weil et al. (1996)} determined that the MYO7A gene contains 48 coding exons. {20:Kelley et al. (1997)} reported that the MYO7A gene spans 120 kb and has 49 exons. textSectionName geneStructure textSectionTitle Gene Function textSectionContent By in situ hybridization analysis in human embryos, {33:Weil et al. (1996)} demonstrated that the MYO7A was expressed in the pigment epithelium and the photoreceptor cells of the retina, indicating to the authors that both cell types may be involved in the retinal degenerative process in Usher syndrome type IB. The gene was also expressed in the human embryonic cochlear and vestibular neuroepithelia. {33:Weil et al. (1996)} suggested that deafness and vestibular dysfunction in Usher syndrome patients results from a defect in the morphogenesis of the inner ear sensory cell stereocilia. {12:El-Amraoui et al. (1996)} found that MYO7A was expressed in human embryo retinal pigment epithelium at 6, 9 and 10 weeks. From 18 to 19 weeks on and in the adult, MYO7A was present in both the pigment epithelium and the photoreceptor cells. MYO7A was mainly present in the inner segments, the base of the outer segments, and the synaptic endings of photoreceptor cells. Myo7a was not expressed in mouse photoreceptor cells, but was expressed in pigment epithelium cells. MYO7A was also expressed in cochlear hair cells during mouse embryonic development and in sensory hair cells in developing human otic vesicle, which correlated with the vestibular and cochlear dysfunctions resulting in balance problems and hearing impairment observed in both Usher patients and shaker-1 mouse mutants. The findings also indicated that the retinal abnormalities in USH1B result from a primary rod and cone defect, and that the shaker-1 mouse phenotype has no retinal defect since Myo7a is absent from the photoreceptor cells in rodents. {7:Boeda et al. (2002)} noted that 3 distinct genetic forms of Usher syndrome, USH1B, USH1D ({601607}), and USH1C ({276904}), are caused by defects in the MYO7A, CDH23 ({605516}), and harmonin (USH1C; {605242}) genes, respectively. They observed severely disorganized hair bundles in shaker-1 mice, and immunohistochemical analysis of differentiating hair cells indicated that Cdh23 was distributed normally in these mice, but harmonin b was not. Using human and mouse cDNA constructs and cells, they provided evidence that harmonin b anchors CDH23 to the stereocilia microfilaments and interacts directly with MYO7A, which conveys harmonin b along the actin core of the developing stereocilia. {7:Boeda et al. (2002)} proposed that the shaping of the hair bundle relies on a functional unit composed of MYO7A, harmonin b, and CDH23 and that the interaction of these proteins ensures the cohesion of the stereocilia. {4:Bahloul et al. (2010)} found that both isoforms of mouse Cdh23 bound directly to the harmonin A isoform and to the tail of myosin-7a. The 3 proteins formed a complex that interacted with phosphatidylinositol 4,5-bisphosphate in synthetic liposomes. Knockout of Cdh23 in mice resulted in loss of harmonin from the apex of hair bundles in the organ of Corti and caused redistribution of a weakened myosin-7a signal along stereocilia. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent Crystal Structure {35:Wu et al. (2011)} reported the crystal structure of the MyTH4-FERM domains of MYO7A in complex with the central domain (CEN) of SANS ({607696}) at 2.8-angstrom resolution. The MyTH4 and FERM domains form an integral structural and functional supramodule binding to 2 highly conserved segments (CEN1 and 2) of SANS. {35:Wu et al. (2011)} concluded that the MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent Usher Syndrome Type IB {31:Weil et al. (1995)} noted that the phenotype of Usher syndrome reflects cytoskeletal abnormalities, including abnormal organization of microtubules in the axoneme of photoreceptor cells (connecting cilium), nasal cilia cells, and sperm cells, as well as widespread degeneration of the organ of Corti. In affected members of 5 unrelated families with Usher syndrome IB, {31:Weil et al. (1995)} identified 5 different mutations in the MYO7A gene ({276903.0001}-{276903.0005}). Among 189 patients with Usher syndrome type I, {34:Weston et al. (1996)} identified 13 different mutations within the N-terminal coding portion of the motor domain of MYO7A. The mutations segregated with the disease in 20 families. Two mutations, R212H ({276903.0004}) and R212C ({276903.0005}), accounted for the greatest percentage of observed mutant alleles (31% or 8/23 alleles). Three patients were homozygotes or compound heterozygotes for mutant alleles. All the other USH1B mutations observed were present in heterozygous state, and it was presumed that the mutation on the other allele was present in unscreened regions of the gene. None of the mutations reported by {34:Weston et al. (1996)} were observed in 96 unrelated control samples. {21:Levy et al. (1997)} designed primers covering the complete MYO7A coding sequence, as well as the 3-prime noncoding sequence, allowing direct sequence analysis of 48 coding exons and flanking splice sites in 7 patients with USH1B. They identified 4 novel mutations. {3:Adato et al. (1997)} screened USH1B families from 12 different ethnic groups for the presence of mutations in all 49 exons of the MYO7A gene. In 15 families, MYO7A mutations were detected, verifying their classification as USH1B. All of these mutations were novel, including 3 missense mutations, 1 premature stop codon, 2 splicing mutations, 1 frameshift, and 1 deletion of more than 2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than 1 family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. None of the 20 known USH1B mutations reported previously in other populations of the world were identified in these families, which although studied in Tel Aviv, were derived from many areas of the world. {27:Ouyang et al. (2005)} carried out a systematic mutation screening of the genes known to cause type I Usher syndrome in patients from the U.S. and U.K. They identified a total of 27 different mutations. Approximately 35 to 39% of the observed mutations involved the USH1B (MYO7A) and USH1D (CDH23; {605516}) genes. Two of the 12 MYO7A mutations they found, R666X ({276903.0016}) and IVS27-1G-C ({276903.0017}), accounted for 38% of the mutations found at that locus. {28:Riazuddin et al. (2008)} identified 17 homozygous mutant alleles in the MYO7A gene, including 14 novel mutations, in affected members of 23 consanguineous Pakistani families with Usher syndrome IB. Nonsyndromic Deafness {24:Liu et al. (1997)} found mutations in the MYO7A gene in 2 of 8 families with autosomal recessive nonsyndromic deafness (DFNB2; {600060}) from the Sichuan province of China. In 1 family, 3 affected sibs were homozygous for an R244P mutation ({276903.0007}). In a Japanese family with autosomal dominant nonsyndromic hearing loss mapping to 11q (DFNA11; {601317}), {25:Liu et al. (1997)} identified a heterozygous mutation in the MYO7A gene ({276903.0011}). All affected members of the family had postlingual bilateral sensorineural hearing loss with subsequent gradual progression. {26:Luijendijk et al. (2004)} identified a heterozygous mutation in the MYO7A gene ({276903.0015}) in affected members of a Dutch family with autosomal dominant nonsyndromic sensorineural deafness. In affected members of a consanguineous Pakistani family with autosomal recessive DFNB2, {28:Riazuddin et al. (2008)} identified a homozygous mutation in the MYO7A gene ({276903.0018}). In 3 sibs, born of consanguineous Iranian parents, with DFNB2, {17:Hildebrand et al. (2010)} identified a homozygous mutation in the MYO7A gene (R395H; {276903.0021}). Associations Pending Confirmation In 4 affected members from a consanguineous Saudi Arabian family with Leber congenital amaurosis (LCA; see {204000}), {30:Wang et al. (2011)} identified homozygosity for a missense mutation in the motor domain of the MYO7A gene (578C-T; T193I) that segregated with disease in the family and was not found in 200 controls or the dbSNP or 1000 Genomes databases. All 4 patients had poor vision since birth, with nystagmus, neuroepithelial atrophy, and nonrecordable electroretinograms. The authors stated that patients in this family did not exhibit hearing loss. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent Digenic inheritance of nonsyndromic deafness had been presented by {5:Balciuniene et al. (1998)} in the case of a Swedish family whose affected members were carriers of DFNA2 ({600101}) and/or DFNA12 ({601543}), both autosomal dominant disorders. Increased severity of deafness was found in family members who were carriers of both alleles. Digenic inheritance was also suggested as one of the possible explanations in the case of DFNB15 (601869). {9:Chen et al. (1997)} observed this autosomal recessive nonsyndromic deafness in a family of Indian origin and found that it was linked to 2 loci, one on 3q and one on 19p. {1:Adato et al. (1999)} found this result interesting in relation to their work because one of the regions of linkage, 3q21.3-q25.2, included the USH3 locus, and the other, 19p13.3-p13.1, included among others the MYO1F gene ({601480}), which codes for another member of the unconventional myosin group. textSectionName genotypePhenotypeCorrelations textSectionTitle Animal Model textSectionContent Shaker-1 (sh1) homozygous mice show hyperactivity, head-tossing and circling due to vestibular dysfunction, as well as neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti. {15:Gibson et al. (1995)} described 3 different mutations in the Myo7a gene that segregated with the disorder in mice. All the mutations were located in the region encoding the myosin head. The sh1 phenotype differs from that of Usher syndrome in humans by the absence of retinal degeneration. {31:Weil et al. (1995)} noted that one form of human neurosensory recessive deafness without retinal dystrophy, DFNB2, maps to 11q in the same general region as USH1B and may represent the human equivalent of sh1. {22:Liu et al. (1998)} demonstrated that mutant Myo7a causes defective distribution of melanosomes in the retinal pigment epithelium (RPE) of shaker-1 mice. Mutant Myo7a was targeted correctly in the RPE, but localization of melanosomes in the apical processes of these epithelial cells depended on proper Myo7A function. Thus, in the RPE, Myo7a has a function similar to that of myosin V (MYPO5A; {160777}), another large unconventional myosin that is necessary for melanosome localization in the dendrites of melanocytes. Given the putative motor properties of Myo7a, it was plausible that melanosomes may be transported along the RPE apical processes as cargo of the molecule. The zebrafish (Danio rerio) possesses 2 mechanosensory organs believed to be homologous to each other: the inner ear, which is responsible for the senses of audition and equilibrium, and the lateral line organ, which is involved in the detection of water movements. Eight zebrafish circler or auditory/vestibular mutants appear to have defects specific to sensory hair cell function. The circler genes may therefore encode components of the mechanotransduction apparatus and/or be the orthologous counterparts of the genes underlying human hereditary deafness. {13:Ernest et al. (2000)} determined that the phenotype of the circler mutant, mariner, is due to mutations in the zebrafish Myo7a homolog. Mariner sensory hair cells displayed morphologic and functional defects similar to those present in mouse shaker-1 hair cells. The findings demonstrated the striking conservation of the function of myosin VIIA throughout vertebrate evolution. In studies of mouse photoreceptor cells with mutant Myo7a, {23:Liu et al. (1999)} presented evidence that myosin VIIa functions in the connecting cilium of photoreceptor cells and participates in the transport of opsin (RHO; {180380}). The findings provided the first direct evidence that opsin travels along the connecting cilium en route to the outer segment and demonstrated that myosin may function in these cilium. Accordingly, abnormal opsin transport may contribute to blindness in Usher syndrome. {8:Boeda et al. (2001)} generated lines of transgenic mice expressing the green fluorescent protein (GFP) reporter gene under the control of several 5-prime-truncated versions of the Myo7a/MYO7A promoter region and intron 1. They obtained transgenic mice with a GFP expression restricted to the hair cells of the inner ear, cochlea, and vestibule. Successive deletions of the promoter defined a minimal sequence of 118 bp that was sufficient, in the presence of intron 1, to target the transgene expression to hair cells. In addition, the deletion of intron 1 from the transgenes abolished hair cell expression, thus indicating the presence of a strong enhancer in the intron. The authors reported that regulatory sequences were sufficient to target the expression of a gene exclusively in sensory cells of the inner ear. To elucidate the role of myosin VIIa in the retina and the basis of photoreceptor degeneration in USH1B patients, {14:Gibbs et al. (2003)} studied mutant phenotypes in the retinas of shaker-1 mice. They reported that the phagocytosis of photoreceptor outer segment discs by the RPE was abnormal in Myo7a-null mice. Both in vivo and in primary cultures of RPE cells, the transport of ingested discs out of the apical region was inhibited in the absence of Myo7a. The results with the cultured RPE cells were the same, irrespective of whether the discs came from wildtype or mutant mice, which demonstrated that the RPE is the source of this defect. The inhibited transport seemed to delay phagosome-lysosome fusion, as the degradation of ingested discs was slower in mutant RPE. Moreover, fewer packets of disc membranes were ingested in vivo, possibly because retarded removal of phagosomes from the apical processes inhibited the ingestion of additional disc membranes. {14:Gibbs et al. (2003)} concluded that myosin VIIa is required for the normal processing of ingested disc membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes. Because the phagocytosis of photoreceptor discs by the RPE had been shown to be critical for photoreceptor cell viability, the authors suggested that this defect likely contributes to the progressive blindness in USH1B. The MYO15 ({602666}), MYO6 ({600970}), and MYO7A genes are essential for hearing in both humans and mice. Despite widespread expression, homozygosity for mutations in these genes only results in auditory or ocular dysfunction. The pirouette (pi) mouse exhibits deafness and inner ear pathology resembling that of Myo15 mutant mice. {19:Karolyi et al. (2003)} crossed Myo15 mutant mice to Myo6, Myo7a, and pi mutant mouse strains. Viable double-mutant homozygotes were obtained from each cross, and hearing in doubly heterozygous mice was similar to singly heterozygous mice. All critical cell types of the cochlear sensory epithelium were present in double-mutant mice, and cochlear stereocilia exhibited a superimposition of single-mutant phenotypes. {19:Karolyi et al. (2003)} suggested that the function of Myo15 is distinct from that of Myo6, Myo7a, or pi in development and/or maintenance of stereocilia. textSectionName animalModel geneMapExists true editHistory terry : 11/07/2012 carol : 11/2/2012 carol : 6/5/2012 mgross : 5/2/2012 alopez : 4/12/2012 carol : 3/9/2012 carol : 12/22/2011 terry : 12/22/2011 ckniffin : 12/21/2011 alopez : 5/10/2011 terry : 5/6/2011 carol : 5/5/2011 terry : 5/3/2011 wwang : 3/2/2011 ckniffin : 2/14/2011 alopez : 2/5/2009 terry : 12/12/2008 terry : 12/2/2008 carol : 10/24/2008 ckniffin : 10/22/2008 carol : 11/2/2007 carol : 5/10/2006 carol : 2/28/2006 wwang : 2/6/2006 terry : 1/31/2006 wwang : 4/6/2005 wwang : 4/4/2005 wwang : 4/1/2005 terry : 3/31/2005 tkritzer : 7/20/2004 terry : 7/14/2004 carol : 3/17/2004 carol : 11/13/2003 tkritzer : 6/26/2003 tkritzer : 6/25/2003 mgross : 3/13/2003 terry : 3/10/2003 cwells : 12/28/2001 cwells : 12/17/2001 carol : 7/20/2001 terry : 11/17/2000 jlewis : 7/15/1999 terry : 6/30/1999 carol : 3/3/1999 terry : 3/1/1999 carol : 2/22/1999 terry : 2/19/1999 terry : 6/4/1998 alopez : 6/1/1998 terry : 5/27/1998 carol : 3/9/1998 joanna : 11/26/1997 terry : 10/28/1997 terry : 10/28/1997 terry : 10/27/1997 jenny : 10/21/1997 terry : 10/17/1997 mark : 6/2/1997 terry : 5/29/1997 mark : 2/28/1997 terry : 2/26/1997 terry : 12/30/1996 terry : 12/20/1996 mark : 10/22/1996 terry : 10/14/1996 mark : 9/6/1996 terry : 5/7/1996 terry : 4/30/1996 mark : 3/14/1996 mark : 3/4/1996 terry : 2/29/1996 terry : 3/22/1995 mimadm : 4/8/1994 carol : 4/6/1994 carol : 3/1/1993 carol : 1/19/1993 carol : 1/7/1993 dateCreated Thu, 07 Jan 1993 03:00:00 EST creationDate Victor A. McKusick : 1/7/1993 epochUpdated 1352275200 dateUpdated Wed, 07 Nov 2012 03:00:00 EST referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63753-7 publisherName Elsevier Science title Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. (Letter) mimNumber 276903 referenceNumber 1 publisherAbbreviation ES pubmedID 10364543 source Am. J. Hum. Genet. 65: 261-265, 1999. authors Adato, A., Kalinski, H., Weil, D., Chaib, H., Korostishevsky, M., Bonne-Tamir, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200831 publisherName Nature Publishing Group title USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. mimNumber 276903 referenceNumber 2 publisherAbbreviation NPG pubmedID 12080385 source Europ. J. Hum. Genet. 10: 339-350, 2002. authors Adato, A., Vreugde, S., Joensuu, T., Avidan, N., Hamalainen, R., Belenkiy, O., Olender, T., Bonne-Tamir, B., Ben-Asher, E., Espinos, C., Millan, J. M., Lehesjoki, A.-E., Flannery, J. G., Avraham, K. B., Pietrovski, S., Sankila, E.-M., Beckmann, J. S., Lancet, D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)64188-3 publisherName Elsevier Science title Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins. mimNumber 276903 referenceNumber 3 publisherAbbreviation ES pubmedID 9382091 source Am. J. Hum. Genet. 61: 813-821, 1997. authors Adato, A., Weil, D., Kalinski, H., Pel-Or, Y., Ayadi, H., Petit, C., Korostishevsky, M., Bonne-Tamir, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20639393 publisherName HighWire Press title Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, for a ternary complex and interact with membrane phospholipids. mimNumber 276903 referenceNumber 4 publisherAbbreviation HighWire pubmedID 20639393 source Hum. Molec. Genet. 19: 3557-3565, 2010. authors Bahloul, A., Michel, V., Hardelin, J.-P., Nouaille, S., Hoos, S., Houdusse, A., England, P., Petit, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61380-9 publisherName Elsevier Science title Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family. mimNumber 276903 referenceNumber 5 publisherAbbreviation ES pubmedID 9718342 source Am. J. Hum. Genet. 63: 786-793, 1998. authors Balciuniene, J., Dahl, N., Borg, E., Samuelsson, E., Koisti, M. J., Pettersson, U., Jazin, E. E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.1335 publisherName John Wiley & Sons, Inc. title From DFNB2 to Usher syndrome: variable expressivity of the same disease. (Letter) mimNumber 276903 referenceNumber 6 publisherAbbreviation Wiley pubmedID 11391666 source Am. J. Med. 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M., Schwender, B. J., Schwartz, M. F., Ramakrishnan, M., Kimberling, W. J., Mooseker, M. S., Corey, D. P. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0890-8508(98)90202-X publisherName Elsevier Science title Detection of a novel cys628-to-stop mutation of the myosin VIIA gene in Usher syndrome type Ib. mimNumber 276903 referenceNumber 11 publisherAbbreviation ES pubmedID 9843659 source Molec. Cell. Probes 12: 417-420, 1998. authors Cuevas, J. M., Espinos, C., Millan, J. M., Sanchez, F., Trujillo, M. J., Garcia-Sandoval, B., Ayuso, C., Najera, C., Beneyto, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8842737 publisherName HighWire Press title Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells. mimNumber 276903 referenceNumber 12 publisherAbbreviation HighWire pubmedID 8842737 source Hum. Molec. Genet. 5: 1171-1178, 1996. authors El-Amraoui, A., Sahly, I., Picaud, S., Sahel. J., Abitbol, M., Petit, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10958658 publisherName HighWire Press title Mariner is defective in myosin VIIA: a zebrafish model for human hereditary deafness. mimNumber 276903 referenceNumber 13 publisherAbbreviation HighWire pubmedID 10958658 source Hum. Molec. Genet. 9: 2189-2196, 2000. authors Ernest, S., Rauch, G.-J., Haffter, P., Geisler, R., Petit, C., Nicolson, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12743369 publisherName HighWire Press title Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. mimNumber 276903 referenceNumber 14 publisherAbbreviation HighWire pubmedID 12743369 source Proc. Nat. Acad. Sci. 100: 6481-6486, 2003. authors Gibbs, D., Kitamoto, J., Williams, D. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/374062a0 publisherName Nature Publishing Group title A type VII myosin encoded by the mouse deafness gene shaker-1. mimNumber 276903 referenceNumber 15 publisherAbbreviation NPG pubmedID 7870172 source Nature 374: 62-64, 1995. authors Gibson, F., Walsh, J., Mburu, P., Varela, A., Brown, K. A., Antonio, M., Beisel, K. W., Steel, K. P., Brown, S. D. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7951250 publisherName HighWire Press title A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. mimNumber 276903 referenceNumber 16 publisherAbbreviation HighWire pubmedID 7951250 source Hum. Molec. Genet. 3: 989-993, 1994. authors Guilford, P., Ayadi, H., Blanchard, S., Chaib, H., Le Paslier, D., Weissenbach, J., Drira, M., Petit, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2010&volume=77&issue=6&spage=563 publisherName Blackwell Publishing title Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation. mimNumber 276903 referenceNumber 17 publisherAbbreviation Blackwell pubmedID 20132242 source Clin. Genet. 77: 563-571, 2010. authors Hildebrand, M. S., Thorne, N. P., Bromhead, C. J., Kahrizi, K., Webster, J. A., Fattahi, Z., Bataejad, M., Kimberling, W. J., Stephan, D., Najmabadi, H., Bahlo, M., Smith, R. J. H. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:2<133::AID-HUMU5>3.0.CO;2-U publisherName John Wiley & Sons, Inc. title Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. mimNumber 276903 referenceNumber 18 publisherAbbreviation Wiley pubmedID 10094549 source Hum. Mutat. 13: 133-140, 1999. authors Janecke, A. R., Meins, M., Sadeghi, M., Grundmann, K., Apfelstedt-Sylla, E., Zrenner, E., Rosenberg, T., Gal, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12966030 publisherName HighWire Press title Myo15 function is distinct from Myo6, Myo7a and pirouette genes in development of cochlear stereocilia. mimNumber 276903 referenceNumber 19 publisherAbbreviation HighWire pubmedID 12966030 source Hum. Molec. Genet. 12: 2797-2805, 2003. authors Karolyi, I. J., Probst, F. J., Beyer, L., Odeh, H., Dootz, G., Cha, K. B., Martin, D. M., Avraham, K. B., Kohrman, D., Dolan, D. F., Raphael, Y., Camper, S. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(96)94545-0 publisherName Elsevier Science title The genomic structure of the gene defective in Usher syndrome type Ib (MYO7A). mimNumber 276903 referenceNumber 20 publisherAbbreviation ES pubmedID 9070921 source Genomics 40: 73-79, 1997. authors Kelley, P. M., Weston, M. D., Chen, Z.-Y., Orten, D. J., Hasson, T., Overbeck, L. D., Pinnt, J., Talmadge, C. B., Ing, P., Mooseker, M. S., Corey, D., Sumegi, J., Kimberling, W. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9002678 publisherName HighWire Press title Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. mimNumber 276903 referenceNumber 21 publisherAbbreviation HighWire pubmedID 9002678 source Hum. Molec. Genet. 6: 111-116, 1997. authors Levy, G., Levi-Acobas, F., Blanchard, S., Gerber, S., Larget-Piet, D., Chenal, V., Liu, X.-Z., Newton, V., Steel, K. P., Brown, S. D. M., Munnich, A., Kaplan, J., Petit, C., Weil, D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/470 publisherName Nature Publishing Group title Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice. (Letter) mimNumber 276903 referenceNumber 22 publisherAbbreviation NPG pubmedID 9620764 source Nature Genet. 19: 117-118, 1998. authors Liu, X., Ondek, B., Williams, D. S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10414956 publisherName HighWire Press title Myosin VIIa participates in opsin transport through the photoreceptor cilium. mimNumber 276903 referenceNumber 23 publisherAbbreviation HighWire pubmedID 10414956 source J. Neurosci. 19: 6267-6274, 1999. authors Liu, X., Udovichenko, I. P., Brown, S. D. M., Steel, K. P., Williams, D. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0697-188 publisherName Nature Publishing Group title Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. mimNumber 276903 referenceNumber 24 publisherAbbreviation NPG pubmedID 9171832 source Nature Genet. 16: 188-190, 1997. authors Liu, X.-Z., Walsh, J., Mburu, P., Kendrick-Jones, J., Cope, M. J. T. V., Steel, K. P., Brown, S. D. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1197-268 publisherName Nature Publishing Group title Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. (Letter) mimNumber 276903 referenceNumber 25 publisherAbbreviation NPG pubmedID 9354784 source Nature Genet. 17: 268-269, 1997. authors Liu, X.-Z., Walsh, J., Tamagawa, Y., Kitamura, K., Nishizawa, M., Steel, K. P., Brown, S. D. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1007/s00439-004-1137-3 publisherName Springer title Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11). mimNumber 276903 referenceNumber 26 publisherAbbreviation Springer pubmedID 15221449 source Hum. Genet. 115: 149-156, 2004. authors Luijendijk, M. W. J., van Wijk, E., Bischoff, A. M. L. C., Krieger, E., Huygen, P. L. M., Pennings, R. J. E., Brunner, H. G., Cremers, C. W. R. J., Cremers, F. P. M., Kremer, H. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1007/s00439-004-1227-2 publisherName Springer title Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. mimNumber 276903 referenceNumber 27 publisherAbbreviation Springer pubmedID 15660226 source Hum. Genet. 116: 292-299, 2005. authors Ouyang, X. M., Yan, D., Du, L. L., Hejtmancik, J. F., Jacobson, S. G., Nance, W. E., Li, A. R., Angeli, S., Kaiser, M., Newton, V., Brown, S. D. M., Balkany, T., Liu, X. Z. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/humu.20677 publisherName John Wiley & Sons, Inc. title Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. mimNumber 276903 referenceNumber 28 publisherAbbreviation Wiley pubmedID 18181211 source Hum. Mutat. 29: 502-511, 2008. authors Riazuddin, S., Nazli, S., Ahmed, Z. M., Yang, Y., Zulfiqar, F., Shaikh, R. S., Zafar, A. U., Khan, S. N., Sabar, F., Javid, F. T., Wilcox, E. R., Tsilou, E., Boger, E. T., Sellers, J. R., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China. mimNumber 276903 referenceNumber 29 pubmedID 21150918 source J. Hum. Genet. 56: 64-70, 2011. authors Sun, Y., Chen, J., Sun, H., Cheng, J., Li, J., Lu, Y., Lu, Y., Jin, Z., Zhu, Y., Ouyang, X., Yan, D., Dai, P., Han, D., Yang, W., Wang, R., Liu, X., Yuan, H. pubmedImages false articleUrl http://dx.doi.org/10.1002/humu.21587 publisherName John Wiley & Sons, Inc. title Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. mimNumber 276903 referenceNumber 30 publisherAbbreviation Wiley pubmedID 21901789 source Hum. Mutat. 32: 1450-1459, 2011. authors Wang, X., Wang, H., Cao, M., Li, Z., Chen, X., Patenia, C., Gore, A., Abboud, E. B., Al-Rajhi, A. A., Lewis, R. A., Lupski, J. R., Mardon, G., Zhang, K., Muzny, D., Gibbs, R. A., Chen, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/374060a0 publisherName Nature Publishing Group title Defective myosin VIIA gene responsible for Usher syndrome type 1B. mimNumber 276903 referenceNumber 31 publisherAbbreviation NPG pubmedID 7870171 source Nature 374: 60-61, 1995. authors Weil, D., Blanchard, S., Kaplan, J., Guilford, P., Gibson, F., Walsh, J., Mburu, P., Varela, A., Levilliers, J., Weston, M. D., Kelley, P. M., Kimberling, W. J., Wagenaar, M., Levi-Acobas, F., Larget-Piet, D., Munnich, A., Steel, K. P., Brown, S. D. M., Petit, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0697-191 publisherName Nature Publishing Group title The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. mimNumber 276903 referenceNumber 32 publisherAbbreviation NPG pubmedID 9171833 source Nature Genet. 16: 191-193, 1997. authors Weil, D., Kussel, P., Blanchard, S., Levy, G., Levi-Acobas, F., Drira, M., Ayadi, H., Petit, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8622919 publisherName HighWire Press title Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. mimNumber 276903 referenceNumber 33 publisherAbbreviation HighWire pubmedID 8622919 source Proc. Nat. Acad. Sci. 93: 3232-3237, 1996. authors Weil, D., Levy, G., Sahly, I., Levi-Acobas, F., Blanchard, S., El-Amraoui, A., Crozet, F., Philippe, H., Abitbol, M., Petit, C. pubmedImages false publisherUrl http://highwire.stanford.edu title Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. mimNumber 276903 referenceNumber 34 pubmedID 8900236 source Am. J. Hum. Genet. 59: 1074-1083, 1996. authors Weston, M. D., Kelley, P. M., Overbeck, L. D., Wagenaar, M., Orten, D. J., Hasson, T., Chen, Z.-Y., Corey, D., Mooseker, M., Sumegi, J., Cremers, C., Moller, C., Jacobson, S. G., Gorin, M. B., Kimberling, W. J. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=21311020 publisherName HighWire Press title Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. mimNumber 276903 referenceNumber 35 publisherAbbreviation HighWire pubmedID 21311020 source Science 331: 757-760, 2011. authors Wu, L., Pan, L., Wei, Z., Zhang, M. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 02043 nbkIDs NBK1434;;Deafness and Hereditary Hearing Loss Overview;;;NBK1265;;Usher Syndrome Type I refSeqAccessionIDs NG_009086.1 uniGenes Hs.370421 approvedGeneSymbols MYO7A nextGxDx true locusSpecificDBs http://www.LOVD.nl/MYO7A;;Retinal and hearing impairment genetic mutation database MYO7A;;;http://www.retina-international.org/files/sci-news/myomut.htm;;Mutations of the Myosin VIIa Gene;;;https://research.cchmc.org/LOVD2/home.php?select_db=MYO7A;;CCHMC Molecular Genetics Laboratory Mutation Database;;;http://www.umd.be/MYO7A/;;The UMD MYO7A mutations database;;;http://webh01.ua.ac.be/hhh/;;Hereditary Hearing Loss Homepage flybaseIDs FBgn0000317 dermAtlas false umlsIDs C1417569 gtr true geneIDs 4647 swissProtIDs Q13402 zfinIDs ZDB-GENE-091110-4,ZDB-GENE-020709-1 ensemblIDs ENSG00000137474,ENST00000409709 geneTests true mgiIDs MGI:104510 ncbiReferenceSequences 530396813,189083797,530396815,189083801,256355178 genbankNucleotideSequences 457254,1613787,1613789,22539728,1235669,14861098,12602312,219518303,71517006,166788573,148174724,148174725,18490795,529605891,511800242,15320474,62088837,225000113,1019444 proteinSequences 119595424,460018219,119595425,119595426,119595427,119595428,1235670,1613788,119595429,1613790,531139,256355179,530396816,166788574,189083798,62088838,578821432,1019445,578821434,225000114,578821436,578821438,189083802 geneticsHomeReferenceIDs gene;;MYO7A;;MYO7A

entryList

entry status live allelicVariantExists true epochCreated 1010390400 geneMap geneSymbols GDAP1, CMT4A, CMT2K, CMTRIA sequenceID 6456 phenotypeMapList phenotypeMap phenotypeMimNumber 607831 mimNumber 606598 phenotypeInheritance Autosomal recessive; Autosomal dominant phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, axonal, type 2K phenotypeMimNumber 607706 mimNumber 606598 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, axonal, with vocal cord paresis phenotypeMimNumber 608340 mimNumber 606598 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, recessive intermediate, A phenotypeMimNumber 214400 mimNumber 606598 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, type 4A chromosomeLocationStart 75262617 chromosomeSort 297 chromosomeSymbol 8 mimNumber 606598 geneInheritance None confidence C mappingMethod Fd, REc geneName Ganglioside-induced differentiation-associated protein 1 mouseMgiID MGI:1338002 mouseGeneSymbol Gdap1 computedCytoLocation 8q21.11 cytoLocation 8q21.11 transcript uc003yah.3 chromosomeLocationEnd 75279344 chromosome 8 contributors Matthew B. Gross - updated : 08/27/2013 Cassandra L. Kniffin - updated : 5/16/2013 Cassandra L. Kniffin - updated : 2/7/2013 Cassandra L. Kniffin - updated : 11/23/2010 Cassandra L. Kniffin - updated : 5/14/2009 Cassandra L. Kniffin - updated : 4/29/2009 Cassandra L. Kniffin - updated : 7/7/2008 George E. Tiller - updated : 2/7/2008 Cassandra L. Kniffin - updated : 9/18/2006 Cassandra L. Kniffin - updated : 5/18/2005 Cassandra L. Kniffin - updated : 2/9/2004 Cassandra L. Kniffin - updated : 12/12/2003 Cassandra L. Kniffin - updated : 5/27/2003 Cassandra L. Kniffin - reorganized : 5/9/2003 Cassandra L. Kniffin - updated : 5/9/2003 Victor A. McKusick - updated : 1/21/2003 Victor A. McKusick - updated : 1/8/2002 clinicalSynopsisExists false mimNumber 606598 allelicVariantList allelicVariant status live name CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A dbSnps rs121908112 text In 2 families with CMT4A ({214400}), {1:Baxter et al. (2002)} found that affected individuals were homozygous for a 92G-A transition in exon 1 of the GDAP1 gene that converted tryptophan-31 to a stop codon (W31X) and was predicted to result in a truncated protein. Affected individuals of the 2 families shared a haplotype surrounding the GDAP1 gene. mutations GDAP1, TRP31TER number 1 clinvarAccessions RCV000004409;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A dbSnps rs104894075 text In a Tunisian family with CMT4A ({214400}), {1:Baxter et al. (2002)} found that affected individuals were homozygous for a nonsense mutation in exon 5 of the GDAP1 gene, ser194 to stop (S194X), which was predicted to result in a truncated protein. This amino acid substitution was the result of a C-to-G transversion at nucleotide 581 (C581G). This family did not share any haplotype over the entire CMT4 region with any other Tunisian family with this disorder. In a consanguineous family, {15:Nelis et al. (2002)} observed homozygosity for this mutation in 2 sisters with autosomal recessive CMT4A. They had onset at ages 2 months and 1 year with foot deformity and hammertoes as the initial symptoms, respectively. At least 1 of them had muscle weakness in both the lower limbs and upper limbs as well as sensory loss and absence of reflexes. {8:Cuesta et al. (2002)} found this mutation in compound heterozygosity with Q163X ({606598.0004}) in a small Spanish family with an axonal CMT phenotype associated with hoarse voice and vocal cord paresis ({607706}). In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; {607831}), {2:Birouk et al. (2003)} identified homozygosity for the S194X mutation in the GDAP1 gene. Vocal cord paresis was not present. mutations GDAP1, SER194TER number 2 alternativeNames CHARCOT-MARIE-TOOTH DISEASE, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE, INCLUDED;; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K, INCLUDED clinvarAccessions RCV000023562;;1;;;RCV000004410;;1;;;RCV000004411;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4A dbSnps rs104894076 text In a Tunisian family with CMT4A ({214400}), {1:Baxter et al. (2002)} found that affected members were homozygous for a 482G-A transition in exon 3 of the GDAP1 gene, resulting in an arg161-to-his (R161H) substitution. mutations GDAP1, ARG161HIS number 3 clinvarAccessions RCV000004412;;1 status live name NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE dbSnps rs104894077 text In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis ({607706}), {8:Cuesta et al. (2002)} found that affected members were homoallelic for a gln163-to-stop (Q163X) mutation in the GDAP1 gene, caused by a C-to-T transition at nucleotide 487. In another smaller family, affected members were compound heterozygotes for the Q163X and S194X ({606598.0002}) mutations in the GDAP1 gene. {3:Boerkoel et al. (2003)} identified homozygosity for the Q163X mutation in 5 patients from 3 unrelated Hispanic families with an early onset form of autosomal recessive CMT. Based on the finding of a common pathogenic haplotype among all patients, the authors suggested that the Q163X mutation is a founder mutation that may have arisen in Spain. Clinical features of these patients included onset at about the first year of life, with severe distal muscle weakness leading to disability in the second decade of life. One patient had vocal cord weakness. Nerve conduction velocities in 2 patients were consistent with axonal CMT. Histopathologic changes showed both demyelination and axonal loss, as well as onion bulb formations. {6:Claramunt et al. (2005)} identified homozygosity for the Q163X mutation in affected probands from 4 unrelated families with axonal neuropathy and vocal cord paresis. All patients were of Spanish ancestry. Haplotype analysis indicated a founder effect originating in the Iberian peninsula approximately 33,000 years ago. mutations GDAP1, GLN163TER number 4 clinvarAccessions RCV000031963;;1;;;RCV000004413;;1 status live name NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE text In a small family of Spanish ancestry, {8:Cuesta et al. (2002)} found that the index member affected by distal axonal neuropathy associated with hoarseness and vocal cord paresis ({607706}) was heteroallelic for a 1-bp insertion, 863insA, in exon 6, leading to a frameshift mutation that generated 2 abnormal amino acids after threonine-288 and terminated the protein at codon 290 (T288fsX290). The 863insA mutation was found in compound heterozygous state with the Q163X mutation ({606598.0004}). mutations GDAP1, 1-BP INS, 863A number 5 clinvarAccessions RCV000004414;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A dbSnps rs28937906 text In 2 sisters with a mixed form of axonal and demyelinating autosomal recessive CMT ({608340}) from a consanguineous Turkish family, {15:Nelis et al. (2002)} identified homozygosity for an 844C-T change in the GDAP1 gene, resulting in an arg282-to-cys (R282C) substitution. The unaffected parents were heterozygous for the mutation. mutations GDAP1, ARG282CYS number 6 clinvarAccessions RCV000004415;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A text In 2 affected members of a consanguineous Turkish family with autosomal recessive intermediate CMT ({608340}), {18:Senderek et al. (2003}) identified homozygosity for a 1-bp insertion (349T) in exon 3 of the GDAP1 gene, resulting in a premature stop codon. mutations GDAP1, 1-BP INS, 349T number 7 clinvarAccessions RCV000004416;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A text In a German girl with autosomal recessive intermediate CMT ({608340}), {18:Senderek et al. (2003)} identified homozygosity for a splice site mutation in the GDAP1 gene (579+1G-A), predicted to result in the skipping of exon 4. mutations GDAP1, IVS4DS, G-A, +1 number 8 clinvarAccessions RCV000004417;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs104894078 text In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT (see {607831}), {6:Claramunt et al. (2005)} identified a heterozygous 358C-T transition in the GDAP1 gene, resulting in an arg120-to-trp (R120W) substitution in a conserved region of the protein. The patients had onset at the end of the second decade and very slow progression, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. {6:Claramunt et al. (2005)} noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. {23:Zimon et al. (2011)} identified a heterozygous R120W substitution in affected members of 3 unrelated families with dominant inheritance of axonal CMT. The families were of Italian, Austrian, and Ashkenazi Jewish descent, respectively. Haplotype analysis indicated a common origin of the mutation, consistent with a founder effect. Expression of the R120W dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, supporting its pathogenicity. The phenotype was considerably variable: age at onset ranged from childhood to adulthood. Walking difficulties were the most common initial symptom and the disorder was slowly progressive, but patients remained ambulatory with mainly distal muscle weakness and atrophy. Two patients also developed proximal weakness. One mutation carrier was asymptomatic, indicating incomplete penetrance. mutations GDAP1, ARG120TRP number 9 clinvarAccessions RCV000004418;;2 status live name CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs104894079 text In a sporadic case of severe axonal CMT2K (see {607831}), {6:Claramunt et al. (2005)} identified a de novo heterozygous 469A-C transversion in the GDAP1 gene, resulting in a thr157-to-pro (T157P) substitution. The patient had early onset of symptoms within the first year of life, moderately reduced distal strength in the lower limbs, absent tendon reflexes, and optic atrophy. mutations GDAP1, THR157PRO number 10 clinvarAccessions RCV000004419;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A dbSnps rs104894080 text In a 39-year-old woman with intermediate CMT ({608340}), {10:Kabzinska et al. (2006)} identified a homozygous 715C-T transition in exon 6 of the GDAP1 gene, resulting in a leu239-to-phe (L239F) substitution. The patient had early onset of a motor and sensory neuropathy leading to severe disability in the third decade of life. {12:Kabzinska et al. (2010)} identified the L239F mutation, either in the homozygous state or in the compound heterozygous state with another pathogenic GDAP1 mutation (see, e.g., R282C; {606598.0006}), in affected individuals from 4 families and in 2 individual patients, all with early-onset autosomal recessive CMT. Five of the families were Polish and 1 was Bulgarian. The age at onset ranged from 2 to 10 years, and all had gait abnormalities due to lower limb weakness and atrophy. Two patients who were homozygous for the L239F mutation became wheelchair-bound as young adults. Electrophysiologic studies showed that most patients had normal motor and sensory nerve conduction velocities, whereas a few had reduced responses. The diagnosis was autosomal recessive sensorimotor axonal neuropathy (CMT2K; {607831}). Haplotype analysis indicated a founder effect for the L239F mutation, indicating that it is prevalent in the Central and Eastern European populations. {12:Kabzinska et al. (2010)} observed that the phenotype resulting from this missense mutation was slightly milder than that associated with GDAP1 nonsense mutations (e.g., S194X; {606598.0002}). mutations GDAP1, LEU239PHE number 11 alternativeNames CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K, INCLUDED clinvarAccessions RCV000034153;;1;;;RCV000033147;;1;;;RCV000004420;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs121908113 text In a Korean father and daughter with late-onset autosomal dominant axonal CMT (see {607831}), {5:Chung et al. (2008)} identified a heterozygous 652C-G transversion in the GDAP1 gene, resulting in a gln218-to-glu (Q218E) substitution in a highly conserved region of the glutathione S-transferase core region of the protein. The mutation was not identified in 374 control chromosomes. The patients had onset of gait difficulties at age 25 and 16 years, respectively. Other features included hand muscle atrophy, decreased distal sensation in the upper and lower limbs, and normal or mildly reduced nerve conduction velocities. Sural nerve biopsy findings in the father were consistent with a primarily axonal process, but there were also signs of demyelination. The phenotype in this family was much milder than that observed in patients with recessive GDAP1 mutations. mutations GDAP1, GLN218GLU number 12 clinvarAccessions RCV000004421;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K dbSnps rs121908114 text In 3 sibs from a consanguineous Amish family with autosomal recessive axonal CMT2K ({607831}), {22:Xin et al. (2008)} identified a homozygous 692C-T transition in exon 5 of the GDAP1 gene, resulting in a pro231-to-leu (P231L) substitution. The patients had childhood onset of distal lower muscle weakness and borderline nerve conduction velocity measurements, consistent with an axonal neuropathy. The disorder was gradually progressive with worsening of the lower limb symptoms, but the patients were still able to do some daily activities in their twenties. There was no vocal cord or hand muscle involvement. The variant was not seen in 100 control chromosomes from a Lancaster County Amish settlement, but was observed in heterozygosity in 7 (14%) of 50 control individuals from a Geauga County Amish settlement. mutations GDAP1, PRO231LEU number 13 clinvarAccessions RCV000004422;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs121908115 text In 4 affected members of a French family with autosomal dominant CMT2K (see {607831}), {4:Cassereau et al. (2009)} identified a heterozygous 719G-A transition in the GDAP1 gene, resulting in a cys240-to-tyr (C240Y) substitution in a conserved residue of the putative GST core region. Mitochondrial respiratory chain complex I activity in patient fibroblasts was 50% lower than controls, but the overall efficiency of ATP production was not affected, indicating compensatory mechanisms. Electron microscopy showed that the tubular mitochondria were 33% larger in diameter and that the mitochondrial mass was 20% greater compared to controls. {4:Cassereau et al. (2009)} concluded that, in addition to the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume. The authors postulated a dominant-negative effect of the C240Y mutation. mutations GDAP1, CYS240TYR number 14 clinvarAccessions RCV000004423;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs267606842 text In an Italian mother and daughter child with autosomal dominant CMT2K (see {607831}), {7:Crimella et al. (2010)} identified a heterozygous 678A-T transversion in exon 5 of the GDAP1 gene, resulting in an arg226-to-ser (R226S) substitution in a highly conserved region in the GST domain. The 25-year-old daughter presented with lower limb involvement at age 8 years and retained independent ambulation. The 49-year-old mother had EMG findings of axonal CMT at age 35 years but showed no clinical signs of the disorder. She developed mild lower limb involvement in her late forties. The mutation was not found in 500 controls. The family illustrated significant intrafamilial variability. mutations GDAP1, ARG226SER number 15 clinvarAccessions RCV000004424;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE A dbSnps rs397515432 text In 2 sisters from a small village in northeast Poland with a mixed form of axonal and demyelinating autosomal recessive CMT ({608340}), {11:Kabzinska et al. (2011)} identified a homozygous 980G-A transition in the GDAP1 gene, resulting in a gly327-to-asp (G327D) substitution in the transmembrane domain, which is important for targeting to the mitochondrial outer membrane. In vitro functional expression studies showed that the mutation interfered with mitochondrial targeting and insertion into the mitochondrial membrane. Cells with overexpression of GDAP1 had a predominantly fragmented mitochondrial morphology, consistent with its role as a mitochondrial fission factor. Cells expressing the G327D mutant protein showed no change in mitochondrial morphology compared to controls, indicating a complete loss of normal fission activity. {11:Kabzinska et al. (2011)} commented that this missense GDAP1 mutation resulted in a severe phenotype usually associated with nonsense mutations, and that the complete loss of fission activity on a cellular level correlates with a severe phenotype. mutations GDAP1, GLY327ASP number 16 clinvarAccessions RCV000033148;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs397515441 text In affected members of 2 distantly related Polish families with dominant CMT2K ({607831}), {23:Zimon et al. (2011)} identified a heterozygous c.467C-G transversion in the GDAP1 gene, resulting in an ala156-to-gly (A156G) substitution at a highly conserved residue. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation was not found in 280 control individuals. Expression of this dominant mutation in HeLa cells resulted in impaired mitochondrial fusion, caused mitochondrial fragmentation, and increased cell sensitivity to apoptosis. The patients had onset in the first or second decades of walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, and all patients remained ambulatory. Nerve conduction velocities showed an axonal pattern. mutations GDAP1, ALA156GLY number 17 clinvarAccessions RCV000043548;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs397515442 text In 3 affected members of a large Finnish family with dominant CMT2K ({607831}), {23:Zimon et al. (2011)} identified a heterozygous c.358A-G transition in the GDAP1 gene, resulting in a his123-to-arg (H123R) substitution. (The nucleotide numbering was based on a revised transcript.) Four older asymptomatic family members also carried the mutation, indicating incomplete penetrance. The mutation was not found in 280 control individuals. The phenotype was variable, with onset of difficulty walking due to distal muscle weakness and atrophy between 3 and 32 years of age. The disorder was slowly progressive, and all patients remained ambulatory. One patient had proximal weakness. Nerve conduction studies showed an axonal pattern. A heterozygous H123R mutation occurred de novo in a patient of Tunisian origin who was more severely affected and showed delayed motor development; that patient had intermediate results on electrophysiologic studies. mutations GDAP1, HIS123ARG number 18 clinvarAccessions RCV000043549;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, TYPE 2K dbSnps rs397515443 text In an Italian father and son with autosomal dominant CMT2K ({607831}), {23:Zimon et al. (2011)} identified a heterozygous 821C-T transition in the GDAP1 gene, resulting in a pro274-to-leu (P274L) substitution at a highly conserved residue in the C-terminal GST domain. The mutation was not found in 280 control individuals. The father, who had onset of distal muscle weakness and atrophy at age 47 years and became wheelchair-bound at age 61, had an intermediate pattern on nerve conduction studies. The son was clinically asymptomatic, but showed an axonal pattern on nerve conduction studies. mutations GDAP1, PRO274LEU number 19 clinvarAccessions RCV000043550;;1 prefix * titles preferredTitle GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1 textSectionList textSection textSectionTitle Description textSectionContent The GDAP1 gene encodes a protein expressed in the central and peripheral nervous system, particularly in Schwann cells. GDAP1 is an integral membrane protein of the outer mitochondrial membrane ({16:Niemann et al., 2005}). textSectionName description textSectionTitle Cloning textSectionContent Gangliosides, sialic acid-containing glycosphingolipids, are abundant in brain tissue, and GD3 synthase (SIAT8; {601123}) plays a key role in their biosynthesis. Using differential display PCR to identify cDNAs induced at different time points by GD3 synthase expression in a mouse neuroblastoma cell line, {14:Liu et al. (1999)} obtained cDNAs encoding 10 Gdap proteins, including Gdap1. The deduced 358-amino acid human GDAP1 protein is 94% identical to the mouse protein, with most divergence at the N terminus. Northern blot analysis revealed expression of a 4.1-kb Gdap1 transcript restricted to mouse brain tissue. Immunofluorescence microscopy demonstrated cytoplasmic expression in mouse cells. {17:Pedrola et al. (2005)} stated that GDAP1 contains 2 N-terminal GST domains and 2 C-terminal transmembrane domains. Real-time PCR of adult rat tissues detected highest expression in spinal cord, dorsal root ganglia, and brain, with low expression in sciatic nerve, and no expression in liver or muscle. GDAP1 localized to the mitochondria in a human neuroblastoma cell line and in COS-7 cells. Western blot analysis of subcellular fractions with anti-GDAP1 antibody detected a 40-kD band corresponding to GDAP1 and an 88-kD band, suggesting that GDAP1 forms a homodimer. The C-terminal transmembrane domains were necessary for correct localization in mitochondria; however, missense mutations did not alter mitochondrial localization. textSectionName cloning textSectionTitle Gene Structure textSectionContent {8:Cuesta et al. (2002)} determined that the GDAP1 gene contains 6 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {22:Xin et al. (2008)} noted that the GDAP1 gene maps to chromosome 8q13.1-q21.1. {9:Gross (2013)} mapped the GDAP1 gene to chromosome 8q21.11 based on an alignment of the GDAP1 sequence (GenBank {GENBANK BC024939}) with the genomic sequence (GRCh37). textSectionName mapping textSectionTitle Gene Function textSectionContent The GDAP1 gene may be involved in a signal transduction pathway in neuronal development. By Northern blot analysis, {8:Cuesta et al. (2002)} showed greatest GDAP1 expression in whole brain and spinal cord. Amplification of human sural nerve and mouse sciatic nerve transcripts suggested that GDAP1 expression does not occur just in neurons but also in Schwann cells. However, GDAP1 expression is higher in central tissues than in peripheral nerves. {16:Niemann et al. (2005)} demonstrated that Gdap1 was expressed in both Schwann cells and neurons of rat peripheral nerve, as well as in various regions of the central nervous system. Subcellular localization studies showed that Gdap1 is an integral membrane protein of the outer mitochondrial membrane. Overexpression of Gdap1 induced fragmentation of mitochondria without inducing apoptosis, affecting overall mitochondrial activity, or interfering with mitochondrial fusion. The mitochondrial fusion proteins, mitofusin-1 (MFN1; {608506}) and -2 (MFN2; {608507}) and Drp1 ({603850}) were able to counterbalance these effects. Gdap1-specific knockdown by RNA interference resulted in a tubular mitochondrial morphology. {16:Niemann et al. (2005)} concluded that GDAP1 regulates mitochondrial dynamics that are critical for the proper function of myelinated peripheral nerves. {17:Pedrola et al. (2005)} found that GST-activity assay detected no activity for soluble GDAP1. {20:Shield et al. (2006)} confirmed that the GDAP1 protein does not have glutathione transferase activity, although it appears to be structurally related to other cytosolic glutathione S-transferases (GST). textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Homozygous or Compound Heterozygous GDAP1 Mutations In 4 different Tunisian families with Charcot-Marie-Tooth disease type 4A (CMT4A; {214400}), an autosomal recessive form of demyelinating peripheral neuropathy mapping to chromosome 8, {1:Baxter et al. (2002)} found homozygosity for 2 nonsense mutations and 1 missense mutation in the GDAP1 gene (W31X, {606598.0001}; S194X, {606598.0002}; R161H, {606598.0003}). In 3 Spanish families reported by {19:Sevilla et al. (2001)} with axonal Charcot-Marie-Tooth neuropathy and vocal cord paresis ({607706}), {8:Cuesta et al. (2002)} identified 3 distinct mutations in the GDAP1 gene (S194X; Q163X, {606598.0004}; 863insA, {606598.0005}). All mutations occurred in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. Thus, mutations in GDAP1 can be associated with both axonal and demyelinating phenotypes, as reported for the myelin protein zero gene (MPZ; {159440}) ({13:Lewis et al., 2000}; {21:Vance, 2000}). {15:Nelis et al. (2002)} pointed out that the mutations in GDAP1 causing early-onset, severe autosomal recessive CMT show a range of nerve conduction velocities with some patients falling in the normal or near normal range, suggesting an axonal neuropathy, whereas others have severely slowed nerve conduction velocities compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show mixed or intermediate features of demyelination and axonal degeneration. In 7 families with autosomal recessive CMT compatible with linkage to the CMT4A locus at 8q21.1, {15:Nelis et al. (2002)} observed homozygosity for 3 distinct mutations in GDAP1 (e.g., R282C, {606598.0006}). In all 4 affected members of a consanguineous Moroccan family with severe axonal CMT (CMT2K; {607831}), {2:Birouk et al. (2003)} identified homozygosity for the S194X mutation in the GDAP1 gene that had previously been identified in patients with CMT4A. {16:Niemann et al. (2005)} showed that disease-associated GDAP1 truncation mutants (S194X and 863insA) were not targeted to the mitochondria and lost mitochondrial fragmentation activity, confirming that the C terminus is important for mitochondrial localization. Disease-associated GDAP1 missense mutants (R161H and R282C) were targeted to the mitochondria but showed some impairment in the ability to induce fragmentation compared to wildtype. Heterozygous GDAP1 Mutations In affected members of 2 unrelated Spanish families with autosomal dominant inheritance of axonal CMT (see {607831}), {6:Claramunt et al. (2005)} identified a heterozygous mutation in the GDAP1 gene (R120W; {606598.0009}). The patients had onset at the end of their second decade and very slow progression of the disorder, which was a milder phenotype than that seen in most patients carrying 2 GDAP1 mutations. {6:Claramunt et al. (2005)} noted that autosomal dominant inheritance had not previously been reported in CMT patients with GDAP1 mutations. {5:Chung et al. (2008)} identified a heterozygous mutation in the GDAP1 gene (Q218E; {606598.0012}) in a Korean father and daughter with autosomal dominant adult-onset axonal CMT2K (see {607831}). The phenotype was milder than that usually observed in patients with recessive GDAP1 mutations. {7:Crimella et al. (2010)} identified 3 different heterozygous mutations in the GDAP1 gene (see, e.g., R226S, {606598.0015}) in 3 (27%) of 11 Italian probands with dominant inheritance of axonal CMT2K. Two of the mutations occurred in the GST domain, and 1 was a truncating mutation resulting in the elimination of the GST domain, suggesting that the GST domain is a frequent target of mutations for the dominant form of CMT2K. {23:Zimon et al. (2011)} reported 8 unrelated families with autosomal dominant CMT due to 4 different heterozygous mutations in the GDAP1 gene ({606598.0009}; {606598.0017}-{606598.0019}). The R120W was found in 3 unrelated families of Italian, Austrian, and Ashkenazi Jewish descent, respectively, and haplotype analysis indicated a founder effect. The phenotype varied considerably, even within a family, and some mutation carriers were asymptomatic, consistent with incomplete penetrance. The age at onset ranged from childhood to adulthood, and the most common initial symptom was walking difficulties due to distal muscle weakness and atrophy. The disorder was slowly progressive, but most patients remained ambulatory. A few patients also developed proximal weakness. The majority of patients had an axonal pattern on electrophysiologic studies, but 2 unrelated patients with a more severe phenotype had an intermediate pattern between axonal and demyelinating. {23:Zimon et al. (2011)} noted that the phenotype in heterozygous GDAP1 mutation carriers was generally milder than that in patients with 2 mutations. textSectionName molecularGenetics geneMapExists true editHistory mgross : 08/27/2013 carol : 8/27/2013 ckniffin : 8/26/2013 carol : 5/28/2013 ckniffin : 5/16/2013 alopez : 2/19/2013 ckniffin : 2/7/2013 wwang : 11/29/2010 ckniffin : 11/23/2010 terry : 9/9/2010 wwang : 5/29/2009 ckniffin : 5/14/2009 wwang : 5/12/2009 ckniffin : 4/29/2009 ckniffin : 1/20/2009 wwang : 7/10/2008 ckniffin : 7/7/2008 wwang : 2/18/2008 terry : 2/7/2008 wwang : 10/2/2006 ckniffin : 9/18/2006 terry : 2/3/2006 wwang : 6/28/2005 wwang : 6/27/2005 ckniffin : 5/18/2005 ckniffin : 4/20/2004 ckniffin : 2/9/2004 carol : 12/12/2003 ckniffin : 12/12/2003 carol : 5/29/2003 ckniffin : 5/27/2003 carol : 5/9/2003 carol : 5/9/2003 ckniffin : 5/2/2003 ckniffin : 5/1/2003 cwells : 1/27/2003 tkritzer : 1/21/2003 terry : 3/11/2002 terry : 3/6/2002 alopez : 1/9/2002 alopez : 1/9/2002 alopez : 1/9/2002 terry : 1/8/2002 mgross : 1/7/2002 dateCreated Mon, 07 Jan 2002 03:00:00 EST creationDate Paul J. Converse : 1/7/2002 epochUpdated 1377586800 dateUpdated Tue, 27 Aug 2013 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1038/ng796 publisherName Nature Publishing Group title Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. mimNumber 606598 referenceNumber 1 publisherAbbreviation NPG pubmedID 11743579 source Nature Genet. 30: 21-22, 2002. authors Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., Hentati, F., Ben Hamida, M., Bel, S., Stenger, J. E., Gilbert, J. R., Pericak-Vance, M. A., Vance, J. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=12707075 publisherName HighWire Press title Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. mimNumber 606598 referenceNumber 2 publisherAbbreviation HighWire pubmedID 12707075 source Arch. Neurol. 60: 598-604, 2003. authors Birouk, N., Azzedine, H., Dubourg, O., Muriel, M.-P., Benomar, A., Hamadouche, T., Maisonobe, T., Ouazzani, R., Brice, A., Yahyaoui, M., Chkili, T., LeGuern, E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.10505 publisherName John Wiley & Sons, Inc. title CMT4A: identification of a Hispanic GDAP1 founder mutation. mimNumber 606598 referenceNumber 3 publisherAbbreviation Wiley pubmedID 12601710 source Ann. Neurol. 53: 400-405, 2003. authors Boerkoel, C. F., Takashima, H., Nakagawa, M., Izumo, S., Armstrong, D., Butler, I., Mancias, P., Papasozomenos, S. C. H., Stern, L. Z., Lupski, J. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1007/s10048-008-0166-9 publisherName Springer title Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). mimNumber 606598 referenceNumber 4 publisherAbbreviation Springer pubmedID 19089472 source Neurogenetics 10: 145-150, 2009. authors Cassereau, J., Chevrollier, A., Gueguen, N., Malinge, M.-C., Letournel, F., Nicolas, G., Richard, L., Ferre, M., Verny, C., Dubas, F., Procaccio, V., Amati-Bonneau, P., Bonneau, D., Reynier, P. pubmedImages false publisherUrl http://www.springeronline.com/ title A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. mimNumber 606598 referenceNumber 5 pubmedID 18231710 source J. Hum. Genet. 53: 360-364, 2008. authors Chung, K. W., Kim, S. M., Sunwoo, I. N., Cho, S. Y., Hwang, S. J., Kim, J., Kang, S. H., Park, K.-D., Choi, K.-G., Choi, I. S., Choi, B.-O. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15805163 publisherName HighWire Press title Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. (Letter) mimNumber 606598 referenceNumber 6 publisherAbbreviation HighWire pubmedID 15805163 source J. Med. Genet. 42: 358-365, 2005. authors Claramunt, R., Pedrola, L., Sevilla, T., Lopez de Munain, A., Berciano, J., Cuesta, A., Sanchez-Navarro, B., Millan, J. M., Saifi, G. M., Lupski, J. R., Vilchez, J. J., Espinos, C., Palau, F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=20685671 publisherName HighWire Press title The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. mimNumber 606598 referenceNumber 7 publisherAbbreviation HighWire pubmedID 20685671 source J. Med. Genet. 47: 712-716, 2010. authors Crimella, C., Tonelli, A., Airoldi, G., Baschirotto, C., D'Angelo, M. G., Bonato, S., Losito, L., Trabacca, A., Bresolin, N., Bassi, M. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng798 publisherName Nature Publishing Group title The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. mimNumber 606598 referenceNumber 8 publisherAbbreviation NPG pubmedID 11743580 source Nature Genet. 30: 22-24, 2002. authors Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., LeGuern, E., Marin, I., Vilchez, J. J., Palau, F. pubmedImages false publisherUrl http://www.nature.com source Baltimore, Md. 8/27/2013. mimNumber 606598 authors Gross, M. B. title Personal Communication. referenceNumber 9 title Early onset Charcot-Marie-Tooth disease caused by a homozygous leu239phe mutation in the GDAP1 gene. mimNumber 606598 referenceNumber 10 pubmedID 17039978 source Acta Myol. 25: 34-37, 2006. authors Kabzinska, D., Drac, H., Rowinska-Marcinska, K., Fidzianska, A., Kochanski, A., Hausmanowa-Petrusewicz, I. pubmedImages false articleUrl http://dx.doi.org/10.1007/s10048-011-0276-7 publisherName Springer title A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe from of AR-CMT2C disease. mimNumber 606598 referenceNumber 11 publisherAbbreviation Springer pubmedID 21365284 source Neurogenetics 12: 145-153, 2011. authors Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1007/s10048-010-0237-6 publisherName Springer title L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype. mimNumber 606598 referenceNumber 12 publisherAbbreviation Springer pubmedID 20232219 source Neurogenetics 11: 357-366, 2010. authors Kabzinska, D., Strugalska-Cynowska, H., Kostera-Pruszczyk, A., Ryniewicz, B., Posmyk, R., Midro, A., Seeman, P., Barankova, L., Zimon, M., Baets, J., Timmerman, V., Guergueltcheva, V., Tournev, I., Sarafov, S., De Jonghe, P., Jordanova, A., Hausmanowa-Petrusewicz, I., Kochanski, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/1097-4598(200010)23:10<1472::AID-MUS3>3.0.CO;2-%23 publisherName John Wiley & Sons, Inc. title Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. mimNumber 606598 referenceNumber 13 publisherAbbreviation Wiley pubmedID 11003782 source Muscle Nerve 23: 1472-1487, 2000. authors Lewis, R. A., Sumner, A. J., Shy, M. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=1999&volume=72&issue=5&spage=1781 publisherName Blackwell Publishing title Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene. mimNumber 606598 referenceNumber 14 publisherAbbreviation Blackwell pubmedID 10217254 source J. Neurochem. 72: 1781-1790, 1999. authors Liu, H., Nakagawa, T., Kanematsu, T., Uchida, T., Tsuji, S. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12499475 publisherName HighWire Press title Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. mimNumber 606598 referenceNumber 15 publisherAbbreviation HighWire pubmedID 12499475 source Neurology 59: 1865-1872, 2002. authors Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., Cuesta, A., Pedrola, L., Palau, F., Gabreels-Festen, A. A. W. M., Verellen, C., Tan, E., Demirci, M., Van Broeckhoven, C., De Jonghe, P., Topaloglu, H., Timmerman, V. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jcb.org/cgi/pmidlookup?view=long&pmid=16172208 publisherName HighWire Press title Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. mimNumber 606598 referenceNumber 16 publisherAbbreviation HighWire pubmedID 16172208 source J. Cell Biol. 170: 1067-1078, 2005. authors Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15772096 publisherName HighWire Press title GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. mimNumber 606598 referenceNumber 17 publisherAbbreviation HighWire pubmedID 15772096 source Hum. Molec. Genet. 14: 1087-1094, 2005. authors Pedrola, L., Espert, A., Wu, X., Claramunt, R., Shy, M. E., Palau, F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12566285 publisherName HighWire Press title Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. mimNumber 606598 referenceNumber 18 publisherAbbreviation HighWire pubmedID 12566285 source Brain 126: 642-649, 2003. authors Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., Zuchner, S., De Jonghe, P., Rudnik-Schoneborn, S., Zerres, K., Schroder, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu source Acta Myol. 20: 49-52, 2001. mimNumber 606598 authors Sevilla, T., Cuesta, A., Chumillas, M. J., Mayordomo, F., Garcia-Planells, J., Palau, F., Vilchez, J. J. title Clinical and genetic studies in three Spanish families with severe autosomal recessive Charcot-Marie-Tooth axonal neuropathy. referenceNumber 19 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(06)01421-5 publisherName Elsevier Science title Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase. mimNumber 606598 referenceNumber 20 publisherAbbreviation ES pubmedID 16857173 source Biochem. Biophys. Res. Commun. 347: 859-866, 2006. authors Shield, A. J., Murray, T. P., Board, P. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=10815126 publisherName HighWire Press title The many faces of Charcot-Marie-Tooth disease. mimNumber 606598 referenceNumber 21 publisherAbbreviation HighWire pubmedID 10815126 source Arch. Neurol. 57: 638-640, 2000. authors Vance, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2008&volume=74&issue=3&spage=274 publisherName Blackwell Publishing title A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family. mimNumber 606598 referenceNumber 22 publisherAbbreviation Blackwell pubmedID 18492089 source Clin. Genet. 74: 274-278, 2008. authors Xin, B., Puffenberger, E., Nye, L., Wiznitzer, M., Wang, H. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=21753178 publisherName HighWire Press title Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. mimNumber 606598 referenceNumber 23 publisherAbbreviation HighWire pubmedID 21753178 source Neurology 77: 540-548, 2011. authors Zimon, M., Baets, J., Fabrizi, G. M., Jaakkola, E., Kabzinska, D., Pilch, J., Schindler, A. B., Cornblath, D. R., Fischbeck, K. H., Auer-Grumbach, M., Guelly, C., Huber, N., De Vriendt, E., Timmerman, V., Suter, U., Hausmanowa-Petrusewicz, I., Niemann, A., Kochanski, A., De Jonghe, P., Jordanova, A. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 05963 nbkIDs NBK1468;;Charcot-Marie-Tooth Neuropathy Type 4;;;NBK1285;;Charcot-Marie-Tooth Neuropathy Type 2;;;NBK1539;;Charcot-Marie-Tooth Neuropathy Type 4A refSeqAccessionIDs NG_008787.2 uniGenes Hs.168950 approvedGeneSymbols GDAP1 nextGxDx true locusSpecificDBs http://gdap1.mitodyn.org;;MITOchondrial DYNamics variation pages;;;http://www.molgen.ua.ac.be/CMTMutations/;;Inherited Peripheral Neuropathies Mutation Database flybaseIDs FBgn0035587 dermAtlas false umlsIDs C1423872 gtr true geneIDs 54332 swissProtIDs Q8TB36 zfinIDs ZDB-GENE-050522-424 ensemblIDs ENSG00000104381,ENST00000220822 geneTests true mgiIDs MGI:1338002 ncbiReferenceSequences 375493488,530388480,375493486,108773796 genbankNucleotideSequences 71517568,194380661,5817211,90926568,511809285,527466517,71051952,19354217,3378205,320461576,148150183,320461571,158258580,320461573,22028364,18875071 proteinSequences 194380662,269849682,19354218,3378206,119607439,119607438,320461577,578815674,158258581,108773799,320461572,108773797,320461574 geneticsHomeReferenceIDs gene;;GDAP1;;GDAP1

entryList

entry status live allelicVariantExists true epochCreated 1042444800 geneMap geneSymbols HGD, AKU sequenceID 2918 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 607474 phenotypeInheritance Autosomal recessive phenotype Alkaptonuria phenotypeMimNumber 203500 chromosomeLocationStart 120347014 chromosomeSort 464 chromosomeSymbol 3 mimNumber 607474 confidence C mappingMethod Fd, H, Psh, A, REc geneName Homogentisate 1,2-dioxygenase (homogentisate oxidase) geneInheritance None computedCytoLocation 3q13.33 cytoLocation 3q13.33 transcript uc003edw.3 chromosomeLocationEnd 120401417 chromosome 3 contributors Matthew B. Gross - updated : 04/25/2014 Cassandra L. Kniffin - updated : 4/21/2014 Victor A. McKusick - updated : 9/12/2003 Victor A. McKusick - updated : 4/22/2003 clinicalSynopsisExists false mimNumber 607474 allelicVariantList allelicVariant status live name ALKAPTONURIA dbSnps rs28942100 text {5:Fernandez-Canon et al. (1996)} studied the HGD gene in 2 unrelated Spanish alkaptonuria (AKU; {203500}) pedigrees. The parents were not consanguineous. Each of the 14 exons composing the HGD gene was PCR-amplified and directly sequenced for each member of the 2 families. In family M, both parents were heterozygous at the HGD locus with a normal allele and an allele carrying a pro230-to-ser (P230S) mutation. The authors noted that pro230 is a conserved residue between the human and fungal proteins. The same 817C-T mutation was found in the second alkaptonuric family (S). The mother was heterozygous for the P230S mutation; the father was heterozygous for a novel allele determining a val300-to-gly substitution ({607474.0002}). The substitution was determined by a 1028T-G transversion in exon 12. The val300 residue is also conserved between the fungal and human proteins. Three alkaptonuric children in this family S but none of 4 healthy children were compound heterozygotes carrying both 817C-T and 1028T-G mutations. The same pro230-to-ser mutation that was found in the HGD gene in mainland Spanish pedigrees was found in an extensively affected kindred in the Canary Islands by {12:Ramos et al. (1998)}. That they were not derived from the same ancestor, however, was suggested by the fact that the 817C-T transition was always associated with a 1219C-T synonymous substitution in the mainland families, which was not found in the Canarian AKU family. {12:Ramos et al. (1998)} also demonstrated that as in the case with the phenylalanine hydroxylase gene ({15:Takahashi et al., 1992}), HGD mutations can be detected by ectopic or illegitimate transcription in tissues where the gene is normally not expressed, making the screening of new mutations easier. Reverse transcription-PCR was used for studying mRNA from urine and blood. mutations HGD, PRO230SER number 1 clinvarAccessions RCV000003315;;2 status live name ALKAPTONURIA dbSnps rs120074170 text See {607474.0001} and {5:Fernandez-Canon et al. (1996)}. mutations HGD, VAL300GLY number 2 clinvarAccessions RCV000003316;;2 status live name ALKAPTONURIA dbSnps rs28941783 text In 2 apparently unrelated Slovakian patients with alkaptonuria (AKU; {203500}), {6:Gehrig et al. (1997)} found homozygosity for a 481G-A transition of the HGD gene leading to a gly161-to-arg (G161R) amino acid substitution. {10:Muller et al. (1999)} found that the G161R substitution was the most prevalent AKU mutation in their cohort of Slovak and Czech patients, accounting for 39.5% of all disease alleles in 19 index patients. {18:Zatkova et al. (2000)} identified this mutation in 8 of 32 chromosomes studied from a Slovak population. mutations HGD, GLY161ARG number 3 clinvarAccessions RCV000003318;;2 status live name ALKAPTONURIA dbSnps rs397515346 text In a Slovakian family with 2 brothers affected with alkaptonuria (AKU; {203500}), {6:Gehrig et al. (1997)} found a 1-bp insertion (454-457insG) in exon 7 of the HGD gene, which led to a premature translational stop 26 codons downstream. mutations HGD, 1-BP INS, 454G number 4 clinvarAccessions RCV000003319;;2 status live name ALKAPTONURIA dbSnps rs397515347 text In 5 alkaptonuria (AKU; {203500}) patients of Slovak and Czech origin, {10:Muller et al. (1999)} found an exchange of the first nucleotide of the splice acceptor site in intron 1 of the HGO gene (183-1G-A), which was likely to abolish effective splicing of exon 2. This was the second most frequent mutation seen in their cohort (the first being G161R, {607474.0003}), representing 13% of all independent AKU alleles studied. mutations HGD, IVS1AS, G-A, -1 number 5 clinvarAccessions RCV000003320;;2 status live name ALKAPTONURIA dbSnps rs587776556 text In a single Finnish pedigree with alkaptonuria (AKU; {203500}), {3:Beltran-Valero de Bernabe et al. (1999)} reported a 1-bp deletion at nucleotide 342 resulting in a frameshift with translation of the first 58 amino acids of the normal HGD protein followed by 31 unrelated amino acids. See also {607474.0011} and {4:Elcioglu et al. (2003)}. mutations HGD, 1-BP DEL, 342A number 6 clinvarAccessions RCV000003321;;1 status live name ALKAPTONURIA dbSnps rs120074171 text In a single Finnish pedigree with alkaptonuria (AKU; {203500}), {3:Beltran-Valero de Bernabe et al. (1999)} reported an G-to-T transversion at nucleotide 1157 of the HGD gene resulting in the substitution of a serine in place of a highly conserved arginine residue. mutations HGD, ARG330SER number 7 clinvarAccessions RCV000003317;;1 status live name ALKAPTONURIA dbSnps rs120074172 text In a single Finnish pedigree with alkaptonuria (AKU; {203500}), {3:Beltran-Valero de Bernabe et al. (1999)} reported an A-to-G transition at nucleotide 1279 resulting in the substitution of an arginine in place of a highly conserved histidine residue. mutations HGD, HIS371ARG number 8 clinvarAccessions RCV000003322;;1 status live name ALKAPTONURIA dbSnps rs120074173 text In 2 families with alkaptonuria (AKU; {203500}), 1 from Germany and the other from France, {1:Beltran-Valero de Bernabe et al. (1998)} identified an A-to-G transition at nucleotide position 1269 of the HGD gene, which resulted in the substitution of valine for a highly conserved methionine at codon 368. {3:Beltran-Valero de Bernabe et al. (1999)} found this mutation in 2 Finnish families. mutations HGD, MET368VAL number 9 clinvarAccessions RCV000003323;;2 status live name ALKAPTONURIA text In 8 of 32 alkaptonuria (AKU; {203500}) chromosomes studied in a Slovak population, {18:Zatkova et al. (2000)} identified a 1-bp insertion at nucleotide 621 of the HGD gene, resulting in frameshift. mutations HGD, 1-BP INS, 621G number 10 clinvarAccessions RCV000003319;;2 status live name ALKAPTONURIA dbSnps rs120074174 text In Turkey, {4:Elcioglu et al. (2003)} described a 39-year-old male patient with typical features of alkaptonuria (AKU; {203500}). In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R) in exon 11 and 342delA ({607474.0006}) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon. Both mutations had been described in other AKU patients and shown experimentally to reduce HGD activity to near null ({10:Muller et al., 1999}; {13:Rodriguez et al., 2000}). mutations HGD, GLY270ARG number 11 clinvarAccessions RCV000003325;;2 prefix * titles alternativeTitles HOMOGENTISIC ACID OXIDASE; HGO preferredTitle HOMOGENTISATE 1,2-DIOXYGENASE; HGD textSectionList textSection textSectionTitle Description textSectionContent The HGD gene encodes homogentisate 1,2-dioxygenase (HGD; {EC 1.13.11.5}), an enzyme involved in the catabolism of phenylalanine and tyrosine (summary by {16:Vilboux et al., 2009}). textSectionName description textSectionTitle Cloning textSectionContent {5:Fernandez-Canon et al. (1996)} cloned the gene for homogentisate 1,2-dioxygenase. Characterization of the human HGD gene came from work with the ascomycete fungus Aspergillus nidulans in which a gene encoding an HGD enzyme, hmgA, had been cloned. The deduced amino acid sequence of its encoded protein product was used to identify EST clones putatively corresponding to the human HGD gene. HGD encodes a 445-amino acid polypeptide with high homology to the Aspergillus hmgA. By Northern blot analysis, {5:Fernandez-Canon et al. (1996)} found highest expression of HGD in the prostate, small intestine, colon, and liver. {14:Schmidt et al. (1997)} cloned the homogentisate 1,2-dioxygenase gene in the mouse. textSectionName cloning textSectionTitle Gene Structure textSectionContent {5:Fernandez-Canon et al. (1996)} determined that the HGD gene contains 14 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {5:Fernandez-Canon et al. (1996)} mapped the HGD gene to chromosome 3q21-q23 by a preliminary PCR screen of hamster/human somatic cell hybrid genomic DNA samples and by fluorescence in situ hybridization. {7:Gross (2014)} mapped the HGD gene to chromosome 3q13.33 based on an alignment of the HGD sequence (GenBank {GENBANK AF000573}) with the genomic sequence (GRCh37). textSectionName mapping textSectionTitle Molecular Genetics textSectionContent In patients with alkaptonuria (AKU; {203500}), {5:Fernandez-Canon et al. (1996)} identified missense mutations in the HGD gene that cosegregated with the disease ({607474.0001}, {607474.0002}), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation. Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, {6:Gehrig et al. (1997)} found 2 novel mutations in the HGD gene. In 2 apparently unrelated patients, a 481G-A substitution was found leading to a gly161-to-arg amino acid substitution ({607474.0003}). Both patients were the only affected members of their families and both were homozygous for this missense mutation. In another pedigree, 2 brothers were homozygous for a 1-basepair insertion (454-457insG) leading to a premature translational stop 26 codons downstream ({607474.0004}); other relatives were heterozygous for the mutation. {1:Beltran-Valero de Bernabe et al. (1998)} reported haplotype and mutation analysis of the HGO gene in 29 previously unstudied AKU chromosomes. They identified 12 novel mutations. Eight were missense mutations, 1 was a frameshift mutation, 2 were intronic mutations, and 1 was a splice site mutation. They also characterized 5 polymorphic sites in HGO and described the haplotypic associations of alleles at these sites in normal and AKU chromosomes. {2:Beltran-Valero de Bernabe et al. (1999)} stated that a total of 17 different AKU mutations had been described. Most of these were missense mutations changing amino acid residues that are conserved between human and other species. Only 3 had been found in more than 1 patient. This remarkable allelic heterogeneity was further demonstrated by analysis of 7 new AKU pedigrees, which uncovered 6 novel AKU mutations and 2 single-nucleotide polymorphisms. Reexamination of all 29 mutations and polymorphisms in the HGO gene described to that time showed that these nucleotide changes were not randomly distributed; the CCC sequence motif and its inverted complement, GGG, were preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in the HGO gene did not involve CpG dinucleotides, which illustrates important differences between the HGO gene and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in the HGO gene, {2:Beltran-Valero de Bernabe et al. (1999)} concluded that the CCC triplet is a mutation hotspot in HGO. {3:Beltran-Valero de Bernabe et al. (1999)} reported 3 novel mutations ({607474.0006}, {607474.0007}, and {607474.0008}) and 1 previously reported mutation, met368 to val ({607474.0009}), in 2 Finnish alkaptonuria pedigrees. Using haplotype analysis, they predicted that the 3 novel mutations were most likely specific to the Finnish population and had arisen recently, in light of the low prevalence of alkaptonuria in Finland and the finding of homozygosity for these mutations in 3 individuals. {10:Muller et al. (1999)} reported on the molecular defects in 30 AKU patients from central Europe. In addition to 5 mutations described previously, they detected 5 novel HGO mutations. In Slovakia, the country with the highest incidence of AKU, they found that 2 recurrent mutations, 183-1G to A ({607474.0005}) and gly161 to arg ({607474.0003}), were found on more than 50% of AKU chromosomes. An analysis of the allelic association with intragenic DNA markers and of the geographic origins of the AKU chromosomes suggested that several independent founders had contributed to the gene pool, and that subsequent genetic isolation was probably responsible for the high prevalence of alkaptonuria in Slovakia. {13:Rodriguez et al. (2000)} reported 7 novel AKU and 22 fungal mutations, and correlated mutational information with HGO crystal structure and function using kinetic assays of AKU mutant enzymes. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. The authors showed how the intra- and intersubunit interactions and the extensive surfaces required for subunit folding and association can be inactivated at multiple levels by single-residue substitutions. {18:Zatkova et al. (2000)} identified 9 different mutations in 32 chromosomes in 17 Slovak patients with alkaptonuria. Four mutations (2 missense, a frameshift, and a splice site mutation) were novel. Gly161 to arg ({607474.0003}) and the 1-bp insertion at nucleotide 621 ({607474.0010}) were each seen in 8 of 32 chromosomes. {11:Phornphutkul et al. (2002)} identified 23 new HGO mutations. In 57 patients, at least 1 HGO mutation was identified; 23 of these mutations had not previously been reported. Thirty-six patients were compound heterozygotes. In total, mutations were identified in 104 of 116 alleles. At least 1 M368V mutation ({607474.0009}) occurred in 14 patients. Seven patients were also either homozygous or heterozygous for H80Q, which is considered a common polymorphism. {17:Zatkova et al. (2003)} stated that 43 HGO mutations had been identified in approximately 100 patients. In Slovakia, the incidence of the disorder was estimated at 1 in 19,000, and 10 different AKU mutations had been identified in this relatively small country. {16:Vilboux et al. (2009)} provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent In the course of an ethylnitrosourea mutation study, {8:Guenet (1990)} and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes. {9:Manning et al. (1999)} demonstrated that the mutation causing alkaptonuria in mice that was created by ethylnitrosourea mutagenesis was a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products. textSectionName animalModel geneMapExists true editHistory mgross : 04/25/2014 mcolton : 4/23/2014 carol : 4/22/2014 mcolton : 4/21/2014 ckniffin : 4/21/2014 carol : 2/8/2006 terry : 8/3/2005 cwells : 9/12/2003 tkritzer : 4/28/2003 terry : 4/22/2003 carol : 1/15/2003 ckniffin : 1/14/2003 dateCreated Mon, 13 Jan 2003 03:00:00 EST creationDate Cassandra L. Kniffin : 1/13/2003 epochUpdated 1398409200 dateUpdated Fri, 25 Apr 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60968-9 publisherName Elsevier Science title Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients. mimNumber 607474 referenceNumber 1 publisherAbbreviation ES pubmedID 9529363 source Am. J. Hum. Genet. 62: 776-784, 1998. authors Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62276-9 publisherName Elsevier Science title Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO). mimNumber 607474 referenceNumber 2 publisherAbbreviation ES pubmedID 10205262 source Am. J. Hum. Genet. 64: 1316-1322, 1999. authors Beltran-Valero de Bernabe, D., Jimenez, F. J., Aquaron, R., Rodriguez de Cordoba, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10594001 publisherName HighWire Press title Mutational analysis of the HGO gene in Finnish alkaptonuria patients. mimNumber 607474 referenceNumber 3 publisherAbbreviation HighWire pubmedID 10594001 source J. Med. Genet. 36: 922-923, 1999. authors Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Alkaptonuria caused by compound heterozygote mutations. mimNumber 607474 referenceNumber 4 pubmedID 12872815 source Genet. Counsel. 14: 207-213, 2003. authors Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0996-19 publisherName Nature Publishing Group title The molecular basis of alkaptonuria. mimNumber 607474 referenceNumber 5 publisherAbbreviation NPG pubmedID 8782815 source Nature Genet. 14: 19-24, 1996. authors Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. pubmedImages false publisherUrl http://www.nature.com title Molecular defects in alkaptonuria. mimNumber 607474 referenceNumber 6 pubmedID 9154114 source Cytogenet. Cell Genet. 76: 14-16, 1997. authors Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W. pubmedImages false source Baltimore, Md. 4/25/2014. mimNumber 607474 authors Gross, M. B. title Personal Communication. referenceNumber 7 source Paris, France 11/5/1990. mimNumber 607474 authors Guenet, J. L. title Personal Communication. referenceNumber 8 articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:2<171::AID-HUMU14>3.0.CO;2-Z publisherName John Wiley & Sons, Inc. title Identification of the mutation in the alkaptonuria mouse model. (Abstract) mimNumber 607474 referenceNumber 9 publisherAbbreviation Wiley pubmedID 10094559 source Hum. Mutat. 13: 171 only, 1999. authors Manning, K., Fernandez-Canon, J. M., Montagutelli, X., Grompe, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200343 publisherName Nature Publishing Group title Allelic heterogeneity of alkaptonuria in Central Europe. mimNumber 607474 referenceNumber 10 publisherAbbreviation NPG pubmedID 10482952 source Europ. J. Hum. Genet. 7: 645-651, 1999. authors Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa021736?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Natural history of alkaptonuria. mimNumber 607474 referenceNumber 11 publisherAbbreviation ATYPON pubmedID 12501223 source New Eng. J. Med. 347: 2111-2121, 2002. authors Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19980630)78:2<192::AID-AJMG20>3.0.CO;2-H publisherName John Wiley & Sons, Inc. title Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood. mimNumber 607474 referenceNumber 12 publisherAbbreviation Wiley pubmedID 9674916 source Am. J. Med. Genet. 78: 192-194, 1998. authors Ramos, S. M., Hernandez, M., Roces, A., Larruga, J. M., Gonzalez, P., Gonzalez, A. M., Pinto, F. M., Cabrera, V. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11001939 publisherName HighWire Press title Structural and functional analysis of mutations in alkaptonuria. mimNumber 607474 referenceNumber 13 publisherAbbreviation HighWire pubmedID 11001939 source Hum. Molec. Genet. 9: 2341-2350, 2000. authors Rodriguez, J. M., Timm, D. E., Titus, G. P., Bertran-Valero de Bernabe, D., Criado, O., Mueller, H. A., Rodriguez de Cordoba, S., Penalva, M. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer-ny.com/link/service/journals/00335/bibs/8n3p168.html publisherName Springer title Cloning of the homogentisate 1,2-dioxygenase gene, the key enzyme of alkaptonuria in mouse. mimNumber 607474 referenceNumber 14 publisherAbbreviation Springer pubmedID 9069115 source Mammalian Genome 8: 168-171, 1997. authors Schmidt, S. R., Gehrig, A., Koehler, M. R., Schmid, M., Muller, C. R., Kress, W. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(92)92665-3 publisherName Elsevier Science title Novel phenylketonuria mutation detected by analysis of ectopically transcribed phenylalanine hydroxylase mRNA from lymphoblast. (Letter) mimNumber 607474 referenceNumber 15 publisherAbbreviation ES pubmedID 1360590 source Lancet 340: 1473 only, 1992. authors Takahashi, K., Kure, S., Matsubara, Y., Narisawa, K. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/humu.21120 publisherName John Wiley & Sons, Inc. title Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. mimNumber 607474 referenceNumber 16 publisherAbbreviation Wiley pubmedID 19862842 source Hum. Mutat. 30: 1611-1619, 2009. authors Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2003&volume=63&issue=2&spage=145 publisherName Blackwell Publishing title Rapid detection methods for five HGO gene mutations causing alkaptonuria. mimNumber 607474 referenceNumber 17 publisherAbbreviation Blackwell pubmedID 12630963 source Clin. Genet. 63: 145-149, 2003. authors Zatkova, A., Chmelikova, A., Polakova, H., Ferakova, E., Kadasi, L. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10970188 publisherName HighWire Press title Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter) mimNumber 607474 referenceNumber 18 publisherAbbreviation HighWire pubmedID 10970188 source J. Med. Genet. 37: 539-542, 2000. authors Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 06315 nbkIDs NBK1454;;Alkaptonuria refSeqAccessionIDs NG_011957.1 uniGenes Hs.368254 approvedGeneSymbols HGD nextGxDx true locusSpecificDBs http://www.alkaptonuria.cib.csic.es/index.htm;;AKUdatabaseHomogentisate 1,2 Dioxygenase Locus (HGO) Mutation and Polymorphism Database Home Page flybaseIDs FBgn0040211 dermAtlas false umlsIDs C1415533 gtr true geneIDs 3081 swissProtIDs Q93099 zfinIDs ZDB-GENE-020802-5 ensemblIDs ENSG00000113924,ENST00000283871 geneTests true ncbiReferenceSequences 296010950,530374527,530374529,530374531 genbankNucleotideSequences 148175670,2953743,148175671,2865608,18088529,190689498,74230053,68984144,23334664,34530051,83112091,82421881,164694752,47939114,8698774,312151119,190690856,2130646,1561615,511853531,158254999,511853534,26006482,1616742 proteinSequences 2865609,193784873,18088530,190689499,1561616,296434531,312151120,115527117,47939115,190690857,158255000,2130647,119599928,530374532,119599929,119599930,530374528,189069305,530374530,1616743 geneticsHomeReferenceIDs gene;;HGD;;HGD

entryList

entry status live allelicVariantExists true epochCreated 952329600 geneMap geneSymbols SLC40A1, SLC11A3, FPN1, IREG1, HFE4 sequenceID 2176 phenotypeMapList phenotypeMap phenotypeMimNumber 606069 mimNumber 604653 phenotypeInheritance None phenotypicSeriesMimNumber 235200 phenotypeMappingKey 3 phenotype Hemochromatosis, type 4 chromosomeLocationStart 190425315 chromosomeSort 678 chromosomeSymbol 2 mimNumber 604653 geneInheritance None confidence C mappingMethod A geneName Solute carrier family 40 (iron-regulated transporter), member 1 mouseMgiID MGI:1315204 mouseGeneSymbol Slc40a1 computedCytoLocation 2q32.2 cytoLocation 2q32 transcript uc002uqp.4 chromosomeLocationEnd 190448477 chromosome 2 contributors Paul J. Converse - updated : 7/2/2014 Patricia A. Hartz - updated : 8/28/2013 Patricia A. Hartz - updated : 5/1/2008 Marla J. F. O'Neill - updated : 9/8/2006 Marla J. F. O'Neill - updated : 3/30/2006 Marla J. F. O'Neill - updated : 7/11/2005 Patricia A. Hartz - updated : 4/19/2005 Ada Hamosh - updated : 1/27/2005 Victor A. McKusick - updated : 11/26/2003 Victor A. McKusick - updated : 1/10/2003 Victor A. McKusick - updated : 9/26/2002 Victor A. McKusick - updated : 1/10/2002 Victor A. McKusick - updated : 6/22/2001 Joanna S. Amberger - updated : 8/7/2000 Stylianos E. Antonarakis - updated : 3/30/2000 clinicalSynopsisExists false mimNumber 604653 allelicVariantList allelicVariant status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893662 text In a large Dutch family with autosomal dominant hemochromatosis ({606069}), {15:Njajou et al. (2001)} identified an A-to-C transversion at nucleotide 734 in exon 5 of the SLC40A1 gene, resulting in an asn144-to-his substitution. mutations SLC40A1, ASN144HIS number 1 clinvarAccessions RCV000005743;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs28939076 text In an Italian family, {12:Montosi et al. (2001)} determined linkage of autosomal dominant hemochromatosis ({606069}) to 2q32 and demonstrated a nonconservative missense mutation in the ferroportin gene: a GCC-to-GAC change resulting in an ala77-to-asp (A77D) substitution. In 147 Indian patients with thalassemia major and 65 cirrhotic controls, {1:Agarwal et al. (2006)} analyzed the SLC40A1 gene and other modifier genes of iron hemostasis and identified the A77D mutation in 3 thalassemia patients, 2 heterozygotes and 1 homozygote. The mutation was not found in the control group. {1:Agarwal et al. (2006)} stated that this was the first report of a ferroportin mutation in the Indian population. mutations SLC40A1, ALA77ASP number 2 clinvarAccessions RCV000005744;;1 status live name HEMOCHROMATOSIS, TYPE 4 text In an Australian family with autosomal dominant hemochromatosis ({606069}), {19:Wallace et al. (2002)} found heterozygosity for a 3-bp (TTG) deletion in exon 5 of the FPN1 gene, resulting in the deletion of valine at position 162. They proposed that the deletion is a loss-of-function mutation that results in impaired iron homeostasis and leads to iron overload. The mutation was present in 2 brothers in whom the diagnosis was made at ages 56 and 73 years and who had hepatic fibrosis. It was also present in the first brother's children: his son, in whom the diagnosis was made at age 20 years and who had mild fibrosis, and his daughter, age 19 years, who had no hepatic abnormality. In the United Kingdom, {5:Devalia et al. (2002)} found the same mutation in members of a family with autosomal dominant hemochromatosis. The proband was a 38-year-old woman who presented with fatigue and was found to have a high serum ferritin concentration and, by liver biopsy, heavy iron deposition in both hepatocytes and Kupffer cells. Venesection therapy was poorly tolerated (i.e., anemia developed), suggesting a defect in iron release from reticuloendothelial stores. The proband's sister likewise had high serum ferritin concentration, and MRI suggested iron accumulation in both the liver and spleen. Liver biopsy showed no fibrosis but marked iron accumulation in Kupffer cells. The combination of erythropoietin administration with phlebotomy permitted removal of iron without anemia. Although details were not provided, other members of the family were affected in a pedigree pattern consistent with autosomal dominant inheritance. The same heterozygous 3-bp deletion in the FPN1 gene was reported by {17:Roetto et al. (2002)} in 2 related Italian patients and in 1 unrelated British patient, suggesting that this is a particularly common mutation in type 4 hemochromatosis. {17:Roetto et al. (2002)} suggested that haploinsufficiency for ferroportin-1 would be more limiting to iron transport in reticuloendothelial cells than in duodenal enterocytes, because the flux of iron through the reticuloendothelial macrophages far exceeds the flux of iron through the duodenal mucosa. {2:Cazzola et al. (2002)} found the same mutation in a family with autosomal dominant hyperferritinemia in whom the proband showed selective iron accumulation in the Kupffer cells on liver biopsy. The mutation occurred in the region of nucleotides 780-791, which comprises 4 TTG repeats; the loss of 1 TTG unit was predicted to result in the deletion of 1 of 3 sequential valine residues, codons 160-162. This is a recurrent mutation, presumably due to slippage mispairing. Affected individuals showed marginally low serum iron and transferrin saturation. Serum ferritin levels were directly related to age, but were 10 to 20 times higher than normal. {2:Cazzola et al. (2002)} suggested that heterozygosity for this mutation represents the prototype of selective reticuloendothelial iron overload, and should be taken into account in the differential diagnosis of hereditary or congenital hyperferritinemias, such as hyperferritinemia-cataract syndrome ({600886}), which is due to mutations in the ferritin light chain gene (FTL; {134790}), or disorders of the ferritin heavy chain gene (FTH1; {134770}). mutations SLC40A1, 3-BP DEL, VAL162DEL number 3 clinvarAccessions RCV000005747;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893663 text In a patient with type 4 hemochromatosis ({606069}), {10:Hetet et al. (2003)} identified an asp157-to-gly (D157G) mutation in the SLC40A1 gene. mutations SLC40A1, ASP157GLY number 4 clinvarAccessions RCV000005745;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893670 text In a patient with type 4 hemochromatosis ({606069}), {10:Hetet et al. (2003)} identified a gln182-to-his (Q182H) mutation in the SLC40A1 gene. The patient's daughter also had increased serum ferritin levels and was found to carry the Q182H mutation. mutations SLC40A1, GLN182HIS number 5 clinvarAccessions RCV000005746;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893671 text In a patient with type 4 hemochromatosis ({606069}), {10:Hetet et al. (2003)} identified a gly323-to-val (G323V) mutation in the SLC40A1 gene. mutations SLC40A1, GLY323VAL number 6 clinvarAccessions RCV000005748;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893672 text In affected members of an Italian family with elevated serum ferritin and low hepcidin/ferritin ratios (HFE4; {606069}), {3:Cemonesi et al. (2005)} identified heterozygosity for an 846A-T transversion in exon 6 of the SLC40A1 gene, resulting in an asp181-to-val (D181V) substitution. A liver biopsy from the 34-year-old male proband revealed heavy iron deposition in both hepatocytes and Kupffer cells. mutations SLC40A1, ASP181VAL number 7 clinvarAccessions RCV000005749;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893673 text In 3 affected members of an Italian family with elevated serum ferritin (HFE4; {606069}), {3:Cemonesi et al. (2005)} identified heterozygosity for a 543G-T transversion in exon 3 of the SLC40A1 gene, resulting in a gly80-to-val (G80V) substitution. mutations SLC40A1, GLY80VAL number 8 clinvarAccessions RCV000005750;;1 status live name HEMOCHROMATOSIS, TYPE 4 dbSnps rs104893664 text In 6 affected members of family of Chinese descent with isolated elevated serum ferritin (HFE4; {606069}), {3:Cemonesi et al. (2005)} identified heterozygosity for a 1104G-A transition in exon 7 of the SLC40A1 gene, resulting in a gly267-to-asp (G267D) substitution. mutations SLC40A1, GLY267ASP number 9 clinvarAccessions RCV000005751;;1 prefix * titles alternativeTitles FERROPORTIN 1; FPN1;; IRON-REGULATED TRANSPORTER 1; IREG1;; SOLUTE CARRIER FAMILY 11 (PROTON-COUPLED DIVALENT METAL ION TRANSPORTER), MEMBER 3, FORMERLY; SLC11A3, FORMERLY preferredTitle SOLUTE CARRIER FAMILY 40 (IRON-REGULATED TRANSPORTER), MEMBER 1; SLC40A1 textSectionList textSection textSectionTitle Cloning textSectionContent Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of the polarized duodenal enterocytes is mediated by the divalent metal transporter, DMT1 ({600523}). A second transporter had been postulated to export iron across the basolateral surface to the circulation. {6:Donovan et al. (2000)} used positional cloning to identify the gene responsible for the hypochromic anemia of the zebrafish mutant 'weissherbst.' The gene, which they called ferroportin-1 (fpn1), encodes a multiple-transmembrane domain protein expressed in the yolk sac that was a candidate for the elusive iron transporter. Zebrafish ferroportin-1 is required for the transport of iron from maternally-derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. {6:Donovan et al. (2000)} isolated mouse and human ferroportin-1 cDNAs by RT-PCR of liver and placenta, respectively. Human ferroportin-1 is a protein of 571 amino acids. A conserved sequence, predicted to form a hairpin-loop structure typical of iron response elements (IREs), was identified in the 5-prime untranslated region of the cDNAs from all 3 species. Northern blot analysis showed the highest level of expression in human placenta, liver, spleen, and kidney. In mouse, primitive erythroblasts derived from the blood islands do not express ferroportin-1, whereas the trophoblast cells of the inner placenta express high levels of ferroportin-1. In the human placenta, ferroportin-1 protein was primarily expressed in a basal location within the syncytiotrophoblasts, suggesting that it transports iron from mother to embryo. Mammalian ferroportin-1 is also expressed at the basolateral surface of duodenal enterocytes. On the basis of basolateral expression pattern of ferroportin-1 in mammalian enterocytes and the implication that ferroportin-1 is required for intestinal iron absorption and iron transport in zebrafish, {6:Donovan et al. (2000)} suggested that the protein is probably involved in iron export from enterocytes in mammals. Iron absorption by the duodenal mucosa is initiated by uptake of ferrous Fe(II) iron across the brush border membrane and culminates in transfer of the metal across the basolateral membrane to the portal vein circulation by an unknown mechanism. Using a subtractive cloning strategy and PCR analysis, {11:McKie et al. (2000)} isolated mouse and human duodenal cDNAs encoding FPN1, which they called iron-regulated transporter-1 (IREG1). The IREG1 protein contains 10 transmembrane domains and is localized to the basolateral membrane of polarized epithelial cells. IREG1 mRNA and protein expression are increased under conditions of increased iron absorption, and the 5-prime untranslated region of the IREG1 mRNA contains a functional IRE. textSectionName cloning textSectionTitle Mapping textSectionContent By FISH, {9:Haile (2000)} mapped the SLC40A1 gene to human chromosome 2q32 and mouse chromosome 1B. textSectionName mapping textSectionTitle Gene Function textSectionContent {11:McKie et al. (2000)} found that IREG1 stimulated iron efflux following expression in Xenopus oocytes. They concluded that IREG1 represents the long-sought duodenal iron export protein and is upregulated in the iron overload disease hereditary hemochromatosis ({235200}). {14:Nemeth et al. (2004)} reported that hepcidin ({606464}) bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. {14:Nemeth et al. (2004)} postulated that the posttranslational regulation of ferroportin by hepcidin may complete a homeostatic loop regulating iron plasma levels and the tissue distribution of iron. {18:Sangokoya et al. (2013)} stated that FPN expression is downregulated in an iron-dependent manner by binding of iron regulatory protein (IRP; see {100880}) to the IRE in the 5-prime UTR of the FPN transcript. Using a reporter gene assay, they confirmed that FPN expression decreased during iron depletion and increased significantly during iron supplementation in human HepG2 hepatocytes. {18:Sangokoya et al. (2013)} also identified a regulatory region in the 3-prime UTR of FPN that bound the microRNA MIR485-3p ({615385}). MIR485-3p was induced during iron deficiency in human cell lines, and MIR485-3p binding to the 3-prime UTR of the FPN transcript repressed FPN translation, leading to increased cellular ferritin (see {134790}) levels and increased cellular iron. Inhibition of MIR485-3p activity or mutation of the MIR485-3p-binding site in the FPN 3-prime UTR relieved FPN repression and led to cellular iron deficiency. IRP and MIR485-3p downregulated FPN expression in an additive manner. {13:Nairz et al. (2013)} found that macrophages from mice lacking nitric oxide synthase-2 (NOS2; {163730}) displayed reduced expression of Fpn1. Nitric oxide upregulated FPN1 expression in mouse and human cells. Nos2-null mouse macrophages had increased iron content due to reduced Fpn1 activity. Reduced Fpn1 expression allowed enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Mice lacking Nos2 or mice in which Nos2 activity was inhibited had increased iron accumulation in spleen and spleen macrophages. Lack of nitric oxide formation resulted in impaired Nrf2 (NFE2L2; {600492}) expression and, consequently, reduced Fpn1 transcription and cellular iron export. Infection of Nos2-null mice or macrophages with S. typhimurium led not only to increased iron accumulation, but also to reduced Tnf ({191160}), Il2 ({147680}), and Ifng ({147570}) expression and impaired pathogen control, all of which could be restored by treatment with iron chelators or overexpression of Fpn1 or Nrf2. {13:Nairz et al. (2013)} concluded that iron accumulation in Nos2-null macrophages counteracts a proinflammatory host response and that the protective effects of nitric oxide partially result from its ability to prevent iron overload in macrophages. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent By mutation analysis of all exons, intron-exon boundaries, and the 5-prime and 3-prime untranslated region (including the IRE) of the SLC40A1 gene in a Dutch family with hemochromatosis type 4 ({606069}), {15:Njajou et al. (2001)} identified a heterozygous A-to-C transversion at nucleotide 734 in exon 5 in all affected individuals. The mutation resulted in an asn144-to-his substitution ({604653.0001}). The substituted asn is a highly conserved amino acid in vertebrates. Independently, in an Italian family with autosomal dominant hemochromatosis originally reported by {16:Pietrangelo et al. (1999)}, {12:Montosi et al. (2001)} mapped the disease locus responsible for autosomal dominant hemochromatosis to 2q32 and recognized ferroportin as a compelling positional candidate for the site of the mutation. They identified a mutation in the SLC40A1 gene ({604653.0002}). They pointed out that the distinguishing features of this disorder, in addition to autosomal dominant inheritance, is early iron accumulation in reticuloendothelial cells and a marked increase in serum ferritin before elevation of the transferrin saturation. {8:Fleming and Sly (2001)} commented that haploinsufficiency for ferroportin would (at least initially) favor low serum iron by decreasing dietary iron absorption and by impairing iron release from macrophages. This could explain the low transferrin saturations, the anemia early in life, and the sensitivity to phlebotomy observed in many of these patients. The hepatocellular iron loading might be explained by the secondary effects of the 'erythropoietic regulator' stimulating intestinal iron absorption, or possibly by ferroportin-1 haploinsufficiency in hepatocytes. Unexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early-onset bilateral cataracts are also present, hereditary hyperferritinemia-cataract syndrome ({600886}), resulting from a heterozygous point mutation in the L ferritin (FTL; {134790}) IRE sequence, can be suspected. {10:Hetet et al. (2003)} sequenced exon 1 of the FTL gene in 52 DNA samples from patients referred for molecular diagnosis of hyperferritinemia-cataract syndrome. They identified 24 samples with a point mutation or deletion in the IRE. For the 28 samples in which no IRE mutation was present, they also genotyped for mutations in the HFE gene ({613609}) and sequenced both the H ferritin (FTH1; {134770}) and SLC40A1 genes. They found an increased frequency (12 of 28) of heterozygotes for the HFE his63-to-asp mutation (H63D; {613609.0002}), but no H ferritin mutations. They identified 3 novel SLC40A1 mutations ({604653.0004}-{604653.0006}), suggesting that these patients had dominant type 4 hemochromatosis. The study demonstrated that both L ferritin IRE and SLC40A1 mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with hereditary hyperferritinemia-cataract syndrome, although the existence of a family history of cataract was only encountered in these patients. This raised the possibility that lens ferritin accumulation may be a factor contributing to age-related cataract in the general population. In transfection experiments using HEK 293T cells, {4:De Domenico et al. (2005)} showed that known human mutations introduced into the mouse Slc40a1 gene generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Coimmunoprecipitation studies revealed that ferroportin is multimeric. Both wildtype and mutant ferroportin participated in the multimer, and mutant ferroportin affected the localization of wildtype ferroportin, its stability, and its response to hepcidin. {4:De Domenico et al. (2005)} concluded that the behavior of mutant ferroportin in cell culture and its ability to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes. {3:Cemonesi et al. (2005)} studied 2 Italian families and 1 of Chinese descent with elevated serum ferritin levels and identified heterozygosity for 3 different mutations in the SLC40A1 gene, respectively. The authors noted the variability in phenotypes between the families and suggested that the mutation ({604653.0007}) in the first Italian family, in which the proband had a liver biopsy showing heavy iron deposition in both hepatocytes and Kupffer cells, likely caused decreased responsiveness to hepcidin, whereas the mutations ({604653.0008} and {604653.0009}) in the latter 2 families likely caused defective localization of the protein to the cell surface. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {7:Donovan et al. (2005)} found that knockout of the ferroportin gene in mice resulted in embryonic lethality, likely from a defect in iron transfer from the mother. Heterozygous animals were viable and showed a mild disruption of iron homeostasis. Mutant mice with ferroportin deleted in all tissues except extraembryonic visceral endoderm and placenta appeared normal at birth, but they developed anemia and abnormal iron accumulation in duodenal enterocytes, Kupffer cells and hepatocytes, and splenic macrophages. Mice with ferroportin deletion restricted to the intestines developed severe iron deficiency anemia. {7:Donovan et al. (2005)} concluded that ferroportin is essential for prenatal and postnatal iron homeostasis, specifically in iron transfer across extraembryonic visceral endoderm, and iron export from enterocytes, macrophages, and hepatocytes. {20:Zohn et al. (2007)} reported the mouse flatiron (ffe) mutation, a his32-to-arg (H32R) substitution in Fpn that affected its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice exhibited iron loading on Kupffer cells, high serum ferritin, and low transferrin saturation. Using macrophages from ffe/+ mice and through expression of Fpn(ffe) in human embryonic kidney cells, {20:Zohn et al. (2007)} showed that Fpn(ffe) acted in a dominant-negative manner and prevented wildtype Fpn from localizing on the cell surface and transporting iron. textSectionName animalModel geneMapExists true editHistory mgross : 07/14/2014 mcolton : 7/2/2014 mgross : 8/28/2013 mgross : 8/28/2013 terry : 3/15/2013 carol : 10/21/2010 mgross : 5/1/2008 wwang : 9/12/2006 terry : 9/8/2006 wwang : 3/31/2006 terry : 3/30/2006 wwang : 7/20/2005 terry : 7/11/2005 mgross : 4/20/2005 terry : 4/19/2005 wwang : 2/2/2005 terry : 1/27/2005 tkritzer : 12/8/2003 tkritzer : 12/3/2003 terry : 11/26/2003 carol : 3/13/2003 carol : 3/13/2003 terry : 3/12/2003 tkritzer : 1/14/2003 terry : 1/10/2003 carol : 10/1/2002 tkritzer : 9/27/2002 tkritzer : 9/26/2002 carol : 1/14/2002 terry : 1/10/2002 mgross : 6/27/2001 terry : 6/22/2001 carol : 8/21/2000 carol : 8/8/2000 joanna : 8/7/2000 alopez : 4/4/2000 mgross : 3/30/2000 alopez : 3/6/2000 dateCreated Mon, 06 Mar 2000 03:00:00 EST creationDate Ada Hamosh : 3/6/2000 epochUpdated 1405321200 dateUpdated Mon, 14 Jul 2014 03:00:00 EDT referenceList reference articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2006&volume=70&issue=1&spage=86 publisherName Blackwell Publishing title Ferroportin (SLC40A1) gene in thalassemic patients of Indian descent. (Letter) mimNumber 604653 referenceNumber 1 publisherAbbreviation Blackwell pubmedID 16813613 source Clin. Genet. 70: 86-87, 2006. authors Agarwal, S., Sankar, V. H., Tewari, D., Pradhan, M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). mimNumber 604653 referenceNumber 2 pubmedID 12406098 source Brit. J. Haemat. 119: 539-546, 2002. authors Cazzola, M., Cremonesi, L., Papaioannou, M., Soriani, N., Kioumi, A., Charalambidou, A., Paroni, R., Romtsou, K., Levi, S., Ferrari, M., Arosio, P., Christakis, J. pubmedImages false articleUrl http://dx.doi.org/10.1111/j.1365-2141.2005.05815.x publisherName Blackwell Publishing title Genetic and clinical heterogeneity of ferroportin disease. mimNumber 604653 referenceNumber 3 publisherAbbreviation Blackwell pubmedID 16351644 source Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit. J. Haemat. 132: 806 only, 2006. authors Cemonesi, L., Forni, G. L., Soriani, N., Lamagna, M., Fermo, I., Daraio, F., Galli, A., Pietra, D., Malcovati, L., Ferrari, M., Camaschella, C., Cazzola, M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15956209 publisherName HighWire Press title The molecular basis of ferroportin-linked hemochromatosis. mimNumber 604653 referenceNumber 4 publisherAbbreviation HighWire pubmedID 15956209 source Proc. Nat. Acad. Sci. 102: 8955-8960, 2005. authors De Domenico, I., Ward, D. M., Nemeth, E., Vaughn, M. B., Musci, G., Ganz, T., Kaplan, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12091367 publisherName HighWire Press title Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). mimNumber 604653 referenceNumber 5 publisherAbbreviation HighWire pubmedID 12091367 source Blood 100: 695-697, 2002. authors Devalia, V., Carter, K., Walker, A. P., Perkins, S. J., Worwood, M., May, A., Dooley, J. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/35001596 publisherName Nature Publishing Group title Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. mimNumber 604653 referenceNumber 6 publisherAbbreviation NPG pubmedID 10693807 source Nature 403: 776-781, 2000. authors Donovan, A., Brownlie, A., Zhou, Y., Shepard, J., Pratt, S. J., Moynihan, J., Paw, B. H., Drejer, A., Barut, B., Zapata, Z., Law, T. C., Brugnara, C., Lux, S. E., Pinkus, G. S., Pinkus, J. L., Kingsley, P. D., Palis, J., Fleming, M. D., Andrews, N. C., Zon, L. I. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1550-4131(05)00030-6 publisherName Elsevier Science title The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. mimNumber 604653 referenceNumber 7 publisherAbbreviation ES pubmedID 16054062 source Cell Metab. 1: 191-200, 2005. authors Donovan, A., Lima, C. A., Pinkus, J. L., Pinkus, G. S., Zon, L. I., Robine, S., Andrews, N. C. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI13739 publisherName Journal of Clinical Investigation title Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. mimNumber 604653 referenceNumber 8 publisherAbbreviation JCI pubmedID 11518724 source J. Clin. Invest. 108: 521-522, 2001. authors Fleming, R. E., Sly, W. S. pubmedImages false publisherUrl http://www.jci.org articleUrl http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=ccg88328 publisherName S. Karger AG, Basel, Switzerland title Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q21 by in situ hybridization. mimNumber 604653 referenceNumber 9 publisherAbbreviation Karger pubmedID 10828623 source Cytogenet. Cell Genet. 88: 328-329, 2000. authors Haile, D. J. pubmedImages false publisherUrl http://www.karger.com articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12730114 publisherName HighWire Press title Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. mimNumber 604653 referenceNumber 10 publisherAbbreviation HighWire pubmedID 12730114 source Blood 102: 1904-1910, 2003. authors Hetet, G., Devaux, I., Soufir, N., Grandchamp, B., Beaumont, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)80425-6 publisherName Elsevier Science title A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. mimNumber 604653 referenceNumber 11 publisherAbbreviation ES pubmedID 10882071 source Molec. Cell 5: 299-309, 2000. authors McKie, A. T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T. J., Farzaneh, F., Hediger, M. A., Hentze, M. W., Simpson, R. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI13468 publisherName Journal of Clinical Investigation title Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. mimNumber 604653 referenceNumber 12 publisherAbbreviation JCI pubmedID 11518736 source J. Clin. Invest. 108: 619-623, 2001. authors Montosi, G., Donovan, A., Totaro, A., Garuti, C., Pignatti, E., Cassanelli, S., Trenor, C. C., Gasparini, P., Andrews, N. C., Pietrangelo, A. pubmedImages false publisherUrl http://www.jci.org articleUrl http://jem.rupress.org/cgi/pmidlookup?view=long&pmid=23630227 publisherName HighWire Press title Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. mimNumber 604653 referenceNumber 13 publisherAbbreviation HighWire pubmedID 23630227 source J. Exp. Med. 210: 855-873, 2013. authors Nairz, M., Schleicher, U., Schroll, A., Sonnweber, T., Theurl, I., Ludwiczek, S., Talasz, H., Brandacher, G., Moser, P. L., Muckenthaler, M. U., Fang, F. C., Bogdan, C., Weiss, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=15514116 publisherName HighWire Press title Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. mimNumber 604653 referenceNumber 14 publisherAbbreviation HighWire pubmedID 15514116 source Science 306: 2090-2093, 2004. authors Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., Kaplan, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/90038 publisherName Nature Publishing Group title A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. mimNumber 604653 referenceNumber 15 publisherAbbreviation NPG pubmedID 11431687 source Nature Genet. 28: 213-214, 2001. authors Njajou, O. T., Vaessen, N., Joosse, M., Berghuis, B., van Dongen, J. W. F., Breuning, M. H., Snijders, P. J. L. M., Rutten, W. P. F., Sandkuijl, L. A., Oostra, B. A., van Duijn, C. M., Heutink, P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199909023411003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. mimNumber 604653 referenceNumber 16 publisherAbbreviation ATYPON pubmedID 10471458 source New Eng. J. Med. 341: 725-732, 1999. authors Pietrangelo, A., Montosi, G., Totaro, A., Garuti, C., Conte, D., Cassanelli, S., Fraquelli, M., Sardini, C., Vasta, F., Gasparini, P. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12123233 publisherName HighWire Press title A valine deletion of ferroportin 1: a common mutation in hemochromatosis type 4? (Letter) mimNumber 604653 referenceNumber 17 publisherAbbreviation HighWire pubmedID 12123233 source Blood 100: 733-734, 2002. authors Roetto, A., Merryweather-Clarke, A. T., Daraio, F., Livesey, K., Pointon, J. J., Barbabietola, G., Piga, A., Mackie, P. H., Robson, K. J. H., Camaschella, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.plos.org/10.1371/journal.pgen.1003408 publisherName Public Library of Science title Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. mimNumber 604653 referenceNumber 18 publisherAbbreviation PLoS pubmedID 23593016 source PLoS Genet. 9: e1003408, 2013. Note: Electronic Article. authors Sangokoya, C., Doss, J. F., Chi, J.-T. pubmedImages false publisherUrl http://www.plos.org/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12091366 publisherName HighWire Press title Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. mimNumber 604653 referenceNumber 19 publisherAbbreviation HighWire pubmedID 12091366 source Blood 100: 692-694, 2002. authors Wallace, D. F., Pedersen, P., Dixon, J. L., Stephenson, P., Searle, J. W., Powell, L. W., Subramaniam, V. N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17289807 publisherName HighWire Press title The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. mimNumber 604653 referenceNumber 20 publisherAbbreviation HighWire pubmedID 17289807 source Blood 109: 4174-4180, 2007. authors Zohn, I. E., De Domenico, I., Pollock, A., Ward, D. M., Goodman, J. F., Liang, X., Sanchez, A. J., Niswander, L., Kaplan, J. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:1315204 mgiHumanDisease false nextGxDx false ncbiReferenceSequences 530370248,187607385,530370246 refSeqAccessionIDs NG_009027.1 dermAtlas false hprdIDs 05229 swissProtIDs Q9NP59 zfinIDs ZDB-GENE-000511-8 uniGenes Hs.643005 gtr true cmgGene false ensemblIDs ENSG00000138449,ENST00000261024 umlsIDs C1456396 genbankNucleotideSequences 22902429,4761673,164692435,117645377,67633295,74230050,62898032,67633305,123979953,13270751,33337961,158257723,7023677,23273531,67633297,67633299,67633301,81481988,67633303,38601957,38601959,148129784,7109248,511860204,57976027,12053382,7264728,123994716,8895484,49065553 geneTests true approvedGeneSymbols SLC40A1 geneIDs 30061 proteinSequences 117645378,22902430,62898033,67633304,123979954,158257724,67633306,7023678,530370249,33337962,67633296,67633298,530370247,67633300,67633302,23273532,38601960,57976028,119631307,38601958,119631306,48428687,7109249,189054570,12053383,62702155,7264729,7657100,123994717,8895485,49065554 geneticsHomeReferenceIDs gene;;SLC40A1;;SLC40A1

entryList

entry status live allelicVariantExists true epochCreated 624178800 geneMap geneSymbols MPL, TPOR, MPLV, THCYT2 sequenceID 407 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 159530 phenotypeInheritance Autosomal dominant phenotype Myelofibrosis with myeloid metaplasia, somatic phenotypeMimNumber 254450 phenotypeMimNumber 601977 mimNumber 159530 phenotypeInheritance Somatic mutation; Autosomal dominant phenotypicSeriesMimNumber 187950 phenotypeMappingKey 3 phenotype Thrombocythemia 2 phenotypeMappingKey 3 mimNumber 159530 phenotypeInheritance Autosomal recessive phenotype Thrombocytopenia, congenital amegakaryocytic phenotypeMimNumber 604498 chromosomeLocationStart 43803474 chromosomeSort 407 chromosomeSymbol 1 mimNumber 159530 geneInheritance None confidence C mappingMethod A geneName Myeloproliferative leukemia virus, homolog of mouseMgiID MGI:97076 mouseGeneSymbol Mpl computedCytoLocation 1p34.2 cytoLocation 1p34 transcript uc001ciw.3 chromosomeLocationEnd 43820134 chromosome 1 contributors Cassandra L. Kniffin - updated : 03/09/2012 Patricia A. Hartz - updated : 1/6/2011 Cassandra L. Kniffin - updated : 2/5/2009 Cassandra L. Kniffin - reorganized : 4/7/2008 Cassandra L. Kniffin - updated : 3/27/2008 Victor A. McKusick - updated : 10/4/2004 Victor A. McKusick - updated : 7/8/2004 Victor A. McKusick - updated : 8/17/2001 Victor A. McKusick - updated : 11/29/2000 Victor A. McKusick - updated : 10/3/2000 Ada Hamosh - updated : 3/10/2000 Victor A. McKusick - updated : 4/20/1999 Victor A. McKusick - updated : 3/12/1998 Victor A. McKusick - updated : 6/12/1997 clinicalSynopsisExists false mimNumber 159530 allelicVariantList allelicVariant status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs121913610 text In a patient with congenital amegakaryocytic thrombocytopenia ({604498}), {8:Ihara et al. (1999)} identified compound heterozygosity for 2 mutations in the MPL gene: a 556C-T transition in exon 4 resulting in a gln186-to-ter (Q186X) substitution, and a 1-bp deletion in exon 10 (1499delT; {159530.0002}) resulting in a frameshift and premature stop codon. mutations MPL, GLN186TER number 1 clinvarAccessions RCV000015217;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL text See {159530.0001} and {8:Ihara et al. (1999)}. mutations MPL, 1-BP DEL, 1499T number 2 clinvarAccessions RCV000015218;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs121913611 text In a 2-year-old Italian boy with congenital amegakaryocytic thrombocytopenia ({604498}), {18:Tonelli et al. (2000)} found compound heterozygosity for 2 MPL mutations. One allele carried a 769C-T transition in exon 5, resulting in an arg257-to-cys (R257C) substitution in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The other allele carried a 1904C-T transition in exon 12, resulting in a pro635-to-leu (P635L; {159530.0004}) substitution in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. TPO plasma levels were greatly increased in the patient. The same patient appears to have been reported by {19:van den Oudenrijn et al. (2000)}. By in vitro cellular studies in K562 human leukemia cells, {17:Tijssen et al. (2008)} demonstrated that the R257C mutant was expressed at the cell surface but resulted in significantly impaired TPO signal transduction. mutations MPL, ARG257CYS number 3 clinvarAccessions RCV000015219;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs121913612 text See {159530.0003} and {18:Tonelli et al. (2000)}. By in vitro cellular studies in K562 human leukemia cells, {17:Tijssen et al. (2008)} demonstrated that the P635L mutant was not properly expressed at the cell surface and resulted in significantly impaired TPO signal transduction. mutations MPL, PRO635LEU number 4 clinvarAccessions RCV000015220;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs28928907 text In a patient with CAMT ({604498}), {19:van den Oudenrijn et al. (2000)} found compound heterozygosity for 2 mutations in the MPL gene: a 305G-C mutation in exon 3, resulting in an arg102-to-pro (R102P) substitution, and a 1473G-A mutation in exon 10 resulting in a trp491-to-ter (W491X; {159530.0006}) substitution. The R102P substitution occurs in the extracellular part of the protein. The patient had low platelet counts from birth onwards, but relatively late development of anemia and leukopenia, consistent with the milder type II phenotype. By in vitro cellular studies in K562 human leukemia cells, {17:Tijssen et al. (2008)} demonstrated that the R102P mutant was expressed at the cell surface but resulted in impaired TPO signal transduction. mutations MPL, ARG102PRO number 5 clinvarAccessions RCV000121539;;0;;;RCV000015221;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs121913613 text See {159530.0005} and {19:van den Oudenrijn et al. (2000)}. mutations MPL, TRP491TER number 6 clinvarAccessions RCV000015222;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL text In a patient with CAMT ({604498}), {19:van den Oudenrijn et al. (2000)} found homozygosity for a G-to-T transversion in the last base of intron 10 of the MPL gene, resulting in loss of the splice site 5-prime of exon 11. mutations MPL, IVS10AS, G-T, -1 number 7 clinvarAccessions RCV000015223;;1 status live name AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL dbSnps rs28928908 text In a patient with CAMT ({604498}), {2:Ballmaier et al. (2001)} found compound heterozygosity for 2 mutations in the MPL gene: an 823C-A transversion in exon 5 resulting in a pro275-to-thr (P275T) substitution, and R102P ({159530.0005}). mutations MPL, PRO275THR number 8 clinvarAccessions RCV000015224;;1 status live name THROMBOCYTHEMIA 2, SUSCEPTIBILITY TO dbSnps rs17292650 text {13:Moliterno et al. (2004)} found that approximately 7% of African Americans are heterozygous for a single nucleotide substitution in the MPL gene, 1238G-T, which results in a lys39-to-asn substitution (K39N). African Americans with the K39N polymorphism, which the authors designated MPL Baltimore, had a significantly higher platelet count than controls without the polymorphism (p less than 0.001) and reduced platelet protein MPL expression. {13:Moliterno et al. (2004)} concluded that K39N represents a functional MPL polymorphism and is associated with altered protein expression of the thrombopoietin receptor and a clinical phenotype of thrombocytosis ({601977}). Individuals who were homozygous for K39N individuals exhibited severe thrombocytosis when compared with appropriate controls. {13:Moliterno et al. (2004)} noted that impaired MPL function in the setting of thrombocytosis is counterintuitive, given the phenotype of marked thrombocytopenia in individuals with loss-of-function MPL mutations, but the authors suggested that MPL may also have a negative regulatory role. mutations MPL, LYS39ASN number 9 clinvarAccessions RCV000121535;;0;;;RCV000015225;;1 status live name THROMBOCYTHEMIA 2 dbSnps rs121913614 text In affected members of a Japanese family with autosomal dominant thrombocythemia-2 ({601977}), {6:Ding et al. (2004)} identified a heterozygous 1073G-A transition in exon 10 of the MPL gene, resulting in a ser505-to-asn (S505N) substitution. Cellular studies showed that mutant cells had increased cytokine-independent survival and constitutively phosphorylated Mek1/2 (see, e.g., {176872}), suggesting that S505N is an activating mutation. {5:Ding et al. (2009)} found that, due to the strong polarity of asparagine, the S505N substitution induced autonomous dimerization of mutant MPL, permitting signal activation in the absence of ligand. mutations MPL, SER505ASN number 10 clinvarAccessions RCV000015226;;1 status live name MYELOFIBROSIS WITH MYELOID METAPLASIA, SOMATIC dbSnps rs121913615 text {16:Pikman et al. (2006)} identified a somatic 1544G-T transversion in the MPL gene, resulting in a trp515-to-leu (W515L) substitution, in 4 (9%) of 45 patients with myelofibrosis with myeloid metaplasia (see {254450}). Two of the patients also had leukocytosis and thrombocytosis at the time of disease presentation. Functional expression studies showed that this was an activating mutation conferring cytokine-independent growth and hypersensitivity to TPHO in cell culture. The W515L mutant protein resulted in constitutive phosphorylation of downstream signaling molecules, including JAK2 ({147796}), STAT3 ({102582}), and ERK ({600997}). Expression of W515L in murine bone marrow resulted in a fully penetrant myeloproliferative disorder with thrombocytosis and extramedullary hematopoiesis. {14:Pardanani et al. (2006)} identified a somatic W515L mutation in 9 patients with myelofibrosis with myeloid metaplasia and in 4 with essential thrombocythemia ({601977}). Six of these patients were also heterozygous for the JAK2 V617F mutation ({147796.0001}), 2 of whom also carried the MPL W515K mutation ({159530.0012}) mutations MPL, TRP515LEU number 11 alternativeNames THROMBOCYTHEMIA 2, SOMATIC, INCLUDED clinvarAccessions RCV000022668;;1;;;RCV000015227;;1 status live name MYELOFIBROSIS WITH MYELOID METAPLASIA, SOMATIC dbSnps rs121913616 text {14:Pardanani et al. (2006)} identified a TG-to-AA mutation in the MPL gene, resulting in a somatic trp515-to-lys (W515K) substitution, in 5 patients with myelofibrosis with myeloid metaplasia (see {254450}). Two of the patients also had the W515L mutation ({159530.0011}) and the JAK2 V617F mutation ({147796.0001}). mutations MPL, TRP515LYS number 12 clinvarAccessions RCV000015228;;1 prefix * titles alternativeTitles THROMBOPOIETIN RECEPTOR; TPOR;; MYELOPROLIFERATIVE LEUKEMIA VIRUS, MOUSE, HOMOLOG OF; MPLV preferredTitle MYELOPROLIFERATIVE LEUKEMIA VIRUS ONCOGENE; MPL textSectionList textSection textSectionTitle Description textSectionContent The MPL gene encodes the receptor for thrombopoietin (THPO; {600044}), a hematopoietic growth factor that regulates the production of multipotent hematopoietic progenitor cells and platelets. {15:Penciolelli et al. (1987)} first identified this protein as a murine retrovirus that causes mouse acute leukemia, and was thus given the name 'myeloproliferative leukemia virus' (MPLV). The phenotype in mice was characterized by rapid proliferation of erythrocytic, granulocytic, and megakaryocytic progenitor cells, resulting in polycythemia, thrombocytosis, and hepatosplenomegaly. MPLV was shown to be a replication-defective, nonsarcomatogenic retrovirus. textSectionName description textSectionTitle Cloning textSectionContent {20:Vigon et al. (1992)} cloned the human homolog of the v-mpl oncogene and found that it showed striking homology with members of the hematopoietin receptor superfamily. They obtained 2 types of clones, termed MPLP and MPLK, which had the same 5-prime extremity but differed in their 3-prime ends. The 2 clones were predicted to encode 635- and 572-residue proteins, respectively. The resulting deduced polypeptides contained a common extracellular domain with a putative signal sequence and a common transmembrane domain but differed in their cytoplasmic domain. The extracellular domain of MPL contains the consensus sequences described for members of the hematopoietin receptor superfamily which include IL5R ({147851}), IL3RA ({308385}), IL4R ({147781}), IL7R ({146661}), IL2RB ({146710}), erythropoietin receptor (EPOR; {133171}), IL6R ({147880}), GMCSF receptor (CSF2R; {306250}), and CSF3R ({138971}). It also shows similarities to the growth hormone receptor (GHR; {600946}) and the prolactin receptor (PRLR; {176761}). Northern blot analysis of a human erythroleukemia cell line identified 2 MPL mRNA transcripts: a major 3.7-kb (MPLP) transcript and a minor 2.8-kb (MPLK) transcript. {11:Mignotte et al. (1994)} described 3 types of mRNA encoding different MPL proteins generated by alternative splicing: the major species contains all 12 exons, whereas mRNAs encoding a protein with a smaller cytoplasmic domain are produced by termination of the transcript within intron 10, and mRNAs encoding a putative soluble form of the MPL protein lack exons 9 and 10. The promoter region is GC-rich and contains putative binding sites for proteins of the ETS and GATA families. textSectionName cloning textSectionTitle Gene Structure textSectionContent {11:Mignotte et al. (1994)} demonstrated that the MPL gene contains 12 exons distributed over 17 kb of DNA. Each of the 2 'cytokine receptor domains' of MPL is encoded by a set of 4 exons, the transmembrane by a single exon, and the cytoplasmic domain by 2 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent By means of in situ hybridization, {10:Le Coniat et al. (1989)} mapped the human MPL gene to chromosome 1p34. textSectionName mapping textSectionTitle Gene Function textSectionContent The mechanism by which TPO activates the TPO receptor appears to be similar to that of other hematopoietic cytokines that bind and induce receptor homodimerization. {4:Cwirla et al. (1997)} identified 2 families of small peptides that bound to human TPOR and competed with the binding of the natural ligand TPO. The sequences of these peptides were not found in the primary sequence of TPO. Further specific screening identified a 14-amino acid peptide with high affinity that stimulated the proliferation of a TPO-responsive cell line. A dimer derived from this peptide stimulated the in vitro proliferation and maturation of megakaryocytes from human bone marrow cells and promoted an increase in platelet count when administered to normal mice. The findings could aid in the development of a recombinant human TPO used for the treatment of thrombocytopenia resulting from chemotherapy and bone marrow transplantation. {12:Moliterno et al. (1998)} found that MPL was markedly reduced or absent in platelets of all 34 patients with polycythemia vera (PV; {263300}) and in 13 of 14 patients with idiopathic myelofibrosis ({254450}). This abnormality appeared to distinguish polycythemia vera from other forms of erythrocytosis. {1:Akashi et al. (2000)} identified a common myeloid progenitor cell that gives rise to all myeloid lineages. The myeloid progenitor did not express IL7R, but did express MPL, whereas the common lymphoid progenitor expressed IL7R but not MPL. Further differentiation of the common myeloid progenitor into the granulocyte/monocyte progenitor versus the megakaryocyte/erythrocyte progenitor was found to be dependent upon expression of the erythropoietin receptor. The commitment of the common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages was proposed to be a mutually exclusive event. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Congenital Amegakaryocytic Thrombocytopenia The considerable similarities between human congenital amegakaryocytic thrombocytopenia (CAMT; {604498}) and murine mpl deficiency prompted {8:Ihara et al. (1999)} to analyze the MPL gene in a patient with CAMT. DNA studies detected compound heterozygosity for 2 mutations in the gene ({159530.0001}; {159530.0002}), both of which were predicted to result in a prematurely terminated MPL protein, which, if translated, would lack all intracellular domains essential for signal transduction. The parents were heterozygous for the mutations. In 8 CAMT patients, {2:Ballmaier et al. (2001)} identified homozygous or compound heterozygous mutations in the MPL gene (see, e.g., {159530.0005}; {159530.0008}). Five patients had complete loss of MPL function, and 3 had missense mutations that were predicted to affect the extracellular domain. Four of the patients were of Kurdish origin and had consanguineous parents. Although all patients had high serum TPO levels, platelets and hematopoietic progenitor cells showed no reactivity to TPO, as measured by testing TPO-synergism to adenosine diphosphate in platelet activation or by megakaryocyte colony assays. Flow cytometry revealed absent surface expression of the TPO receptor MPL in all 3 patients analyzed. Role in Myeloproliferative Disorders {13:Moliterno et al. (2004)} identified a heterozygous SNP in the MPL gene (K39N; {159530.0009}), designated 'MPL Baltimore,' in approximately 7% of African Americans. Three African American women referred for evaluation of a chronic myeloproliferative disorder (MPD) were found to be heterozygous for K39N. Further studies showed that African Americans with the K39N polymorphism had a significantly higher platelet count than controls without the polymorphism (p less than 0.001) and reduced platelet protein MPL expression. Expression of MPL cDNA containing the K39N substitution in cell lines was associated with incomplete processing and a reduction in MPL protein. {13:Moliterno et al. (2004)} concluded that K39N represents a functional MPL polymorphism and is associated with altered protein expression of the thrombopoietin receptor and a clinical phenotype of thrombocytosis (THCYT2; {601977}). Individuals who were homozygous for K39N individuals exhibited severe thrombocytosis when compared with appropriate controls. {13:Moliterno et al. (2004)} noted that impaired MPL function in the setting of thrombocytosis is counterintuitive, given the phenotype of marked thrombocytopenia in individuals with loss-of-function MPL mutations, but the authors suggested that MPL may also have a negative regulatory role. The K39N substitution was restricted to African Americans. In affected members of a Japanese family with autosomal dominant essential thrombocythemia, {6:Ding et al. (2004)} identified a heterozygous activating germline mutation in the MPL gene ({159530.0010}). {16:Pikman et al. (2006)} and {14:Pardanani et al. (2006)} independently identified gain-of-function somatic mutations in codon 515 of the MPL gene (W515L, {159530.0011}; W515K, {159530.0012}) in patients with myelofibrosis with myeloid metaplasia (see {254450}) and/or essential thrombocythemia. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {7:Gurney et al. (1994)} found that Mpl-null mice had an 85% decrease in the number of platelets and megakaryocytes but had normal amounts of other hematopoietic cell types. These mice also had increased concentrations of circulating TPO. These results showed that MPL specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO. {9:Kimura et al. (1998)} found that mice lacking Mpl have hematopoietic stem cell deficiencies that are not limited to the megakaryocytic lineage. Their findings imply that TPO, signaling through MPL, plays a vital physiologic role in the regulation of hematopoietic stem cell production and function. {3:Carpinelli et al. (2004)} performed a suppressor screen in Mpl-null mice using N-ethyl-N-nitrosourea (ENU) mutagenesis. They showed that mutations in the Myb gene ({189990}) caused a myeloproliferative syndrome and supraphysiologic expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. textSectionName animalModel geneMapExists true editHistory carol : 03/09/2012 ckniffin : 3/8/2012 mgross : 1/6/2011 terry : 1/6/2011 wwang : 2/17/2009 ckniffin : 2/5/2009 carol : 9/15/2008 carol : 6/18/2008 carol : 4/18/2008 carol : 4/8/2008 carol : 4/7/2008 ckniffin : 3/27/2008 carol : 2/8/2007 terry : 3/16/2005 tkritzer : 10/8/2004 terry : 10/4/2004 tkritzer : 7/20/2004 tkritzer : 7/8/2004 terry : 7/8/2004 mcapotos : 8/28/2001 mcapotos : 8/17/2001 mcapotos : 12/18/2000 mcapotos : 12/13/2000 terry : 11/29/2000 mcapotos : 10/12/2000 mcapotos : 10/9/2000 terry : 10/3/2000 alopez : 3/10/2000 mgross : 2/4/2000 jlewis : 7/27/1999 mgross : 4/27/1999 mgross : 4/22/1999 terry : 4/20/1999 psherman : 3/12/1998 psherman : 3/12/1998 psherman : 3/12/1998 terry : 3/6/1998 mark : 6/12/1997 terry : 6/10/1997 mimadm : 12/2/1994 carol : 9/22/1994 carol : 10/1/1993 carol : 7/7/1992 supermim : 3/16/1992 carol : 6/24/1991 dateCreated Thu, 12 Oct 1989 03:00:00 EDT creationDate Victor A. McKusick : 10/12/1989 epochUpdated 1331280000 dateUpdated Fri, 09 Mar 2012 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1038/35004599 publisherName Nature Publishing Group title A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. mimNumber 159530 referenceNumber 1 publisherAbbreviation NPG pubmedID 10724173 source Nature 404: 193-197, 2000. authors Akashi, K., Traver, D., Miyamoto, T., Weissman, I. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11133753 publisherName HighWire Press title c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. mimNumber 159530 referenceNumber 2 publisherAbbreviation HighWire pubmedID 11133753 source Blood 97: 139-146, 2001. authors Ballmaier, M., Germeshausen, M., Schulze, H., Cherkaoui, K., Lang, S., Gaudig, A., Krukemeier, S., Eilers, M., Straub, G., Welte, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15071178 publisherName HighWire Press title Suppressor screen in Mpl -/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. mimNumber 159530 referenceNumber 3 publisherAbbreviation HighWire pubmedID 15071178 source Proc. Nat. Acad. Sci. 101: 6553-6558, 2004. authors Carpinelli, M. R., Hilton, D. J., Metcalf, D., Antonchuk, J. L., Hyland, C. D., Mifsud, S. L., Di Rago, L., Hilton, A. A., Willson, T. A., Roberts, A. W., Ramsay, R. G., Nicola, N. A., Alexander, W. S. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=9180079 publisherName HighWire Press title Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. mimNumber 159530 referenceNumber 4 publisherAbbreviation HighWire pubmedID 9180079 source Science 276: 1696-1699, 1997. authors Cwirla, S. E., Balasubramanian, P., Duffin, D. J., Wagstrom, C. R., Gates, C. M., Singer, S. C., Davis, A. M., Tansik, R. L., Mattheakis, L. C., Boytos, C. M., Schatz, P. J., Baccanari, D. P., Wrighton, N. C., Barrett, R. W., Dower, W. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=19483125 publisherName HighWire Press title The asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. mimNumber 159530 referenceNumber 5 publisherAbbreviation HighWire pubmedID 19483125 source Blood 114: 3325-3328, 2009. authors Ding, J., Komatsu, H., Iida, S., Yano, H., Kusumoto, S., Inagaki, A., Mori, F., Ri, M., Ito, A., Wakita, A., Ishida, T., Nitta, M., Ueda, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=14764528 publisherName HighWire Press title Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. mimNumber 159530 referenceNumber 6 publisherAbbreviation HighWire pubmedID 14764528 source Blood 103: 4198-4200, 2004. authors Ding, J., Komatsu, H., Wakita, A., Kato-Uranishi, M., Ito, M., Satoh, A., Tsuboi, K., Nitta, M., Miyazaki, H., Iida, S., Ueda, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8073287 publisherName HighWire Press title Thrombocytopenia in c-mpl-deficient mice. mimNumber 159530 referenceNumber 7 publisherAbbreviation HighWire pubmedID 8073287 source Science 265: 1445-1447, 1994. authors Gurney, A. L., Carver-Moore, K., de Sauvage, F. J., Moore, M. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10077649 publisherName HighWire Press title Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. mimNumber 159530 referenceNumber 8 publisherAbbreviation HighWire pubmedID 10077649 source Proc. Nat. Acad. Sci. 96: 3132-3136, 1999. authors Ihara, K., Ishii, E., Eguchi, M., Takada, H., Suminoe, A., Good, R. A., Hara, T. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9448308 publisherName HighWire Press title Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. mimNumber 159530 referenceNumber 9 publisherAbbreviation HighWire pubmedID 9448308 source Proc. Nat. Acad. Sci. 95: 1195-1200, 1998. authors Kimura, S., Roberts, A. W., Metcalf, D., Alexander, W. S. pubmedImages true publisherUrl http://highwire.stanford.edu title The human homolog of the myeloproliferative virus maps to chromosome band 1p34. mimNumber 159530 referenceNumber 10 pubmedID 2550356 source Hum. Genet. 83: 194-196, 1989. authors Le Coniat, M., Souyri, M., Vigon, I., Wendling, F., Tambourin, P., Berger, R. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888754384711207 publisherName Elsevier Science title Structure and transcription of the human c-mpl gene (MPL). mimNumber 159530 referenceNumber 11 publisherAbbreviation ES pubmedID 8020956 source Genomics 20: 5-12, 1994. authors Mignotte, V., Vigon, I., Boucher de Crevecoeur, E., Romeo, P.-H., Lemarchandel, V., Chretien, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199802263380903?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. mimNumber 159530 referenceNumber 12 publisherAbbreviation ATYPON pubmedID 9475764 source New Eng. J. Med. 338: 572-580, 1998. authors Moliterno, A. R., Hankins, W. D., Spivak, J. L. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15269348 publisherName HighWire Press title Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. mimNumber 159530 referenceNumber 13 publisherAbbreviation HighWire pubmedID 15269348 source Proc. Nat. Acad. Sci. 101: 11444-11447, 2004. authors Moliterno, A. R., Williams, D. M., Gutierrez-Alamillo, L. I., Salvatori, R., Ingersoll, R. G., Spivak, J. L. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=16868251 publisherName HighWire Press title MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. mimNumber 159530 referenceNumber 14 publisherAbbreviation HighWire pubmedID 16868251 source Blood 108: 3472-3476, 2006. authors Pardanani, A. D., Levine, R. L., Lasho, T., Pikman, Y., Mesa, R. A., Wadleigh, M., Steensma, D. P., Elliott, M. A., Wolanskyj, A. P., Hogan, W. J., McClure, R. F., Litzow, M. R., Gilliland, D. G., Tefferi, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=3027384 publisherName HighWire Press title Genetic analysis of myeloproliferative leukemia virus, a novel acute leukemogenic replication-defective retrovirus. mimNumber 159530 referenceNumber 15 publisherAbbreviation HighWire pubmedID 3027384 source J. Virol. 61: 579-583, 1987. authors Penciolelli, J. F., Wendling, F., Robert-Lezenes, J., Barque, J. F., Tambourin, P., Gisselbrecht, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.plos.org/10.1371/journal.pmed.0030270 publisherName Public Library of Science title MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. mimNumber 159530 referenceNumber 16 publisherAbbreviation PLoS pubmedID 16834459 source PLoS Med. 3: e270, 2006. Note: Electronic Article. authors Pikman, Y., Lee, B. H., Mercher, T., McDowell, E., Ebert, B. L., Gozo, M., Cuker, A., Wernig, G., Moore, S., Galinsky, I., DeAngelo, D. J., Clark, J. J., Lee, S. J., Golub, T. R., Wadleigh, M., Gilliland, D. G., Levine, R. L. pubmedImages true publisherUrl http://www.plos.org/ source Brit. J. Haematol. 141: 808-813, 2008. mimNumber 159530 authors Tijssen, M. R., di Summa, F., van den Oudenrijn, S., Zwaginga, J. J., van der Schoot, C. E., Voermans, C., de Haas, M. title Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia. referenceNumber 17 articleUrl http://link.springer.de/link/service/journals/00439/bibs/0107003/01070225.htm publisherName Springer title Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). mimNumber 159530 referenceNumber 18 publisherAbbreviation Springer pubmedID 11071383 source Hum. Genet. 107: 225-233, 2000. authors Tonelli, R., Scardovi, A. L., Pession, A., Strippoli, P., Bonsi, L., Vitale, L., Prete, A., Locatelli, F., Bagnara, G. P., Paolucci, G. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=2000&volume=110&issue=2&spage=441 publisherName Blackwell Publishing title Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. mimNumber 159530 referenceNumber 19 publisherAbbreviation Blackwell pubmedID 10971406 source Brit. J. Haemat. 110: 441-448, 2000. authors van den Oudenrijn, S., Bruin, M., Folman, C. C., Peters, M., Faulkner, L. B., de Haas, M., van dem Borne, A. E. G. K. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1608974 publisherName HighWire Press title Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. mimNumber 159530 referenceNumber 20 publisherAbbreviation HighWire pubmedID 1608974 source Proc. Nat. Acad. Sci. 89: 5640-5644, 1992. authors Vigon, I., Mornon, J.-P., Cocault, L., Mitjavila, M.-T., Tambourin, P., Gisselbrecht, S., Souyri, M. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:97076 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 172072641,530362643 refSeqAccessionIDs NG_007525.1 dermAtlas false hprdIDs 01161 swissProtIDs P40238 zfinIDs ZDB-GENE-060421-1 uniGenes Hs.82906 gtr true cmgGene false umlsIDs C0812295 genbankNucleotideSequences 148141205,1546806,148141206,1546805,1546804,1546803,184262,184260,78191534,147897688,511871787,511871784,74230049,7529223,592748354,157169669 geneTests true approvedGeneSymbols MPL geneIDs 4352 proteinSequences 184263,78191535,184261,147897689,1546809,1546808,730980,119627509,119627508,119627510,592748355,157169670,4885491 geneticsHomeReferenceIDs gene;;MPL;;MPL locusSpecificDBs http://www.LOVD.nl/MPL;;Mendelian genes (MPL2)

entryList

entry status live allelicVariantExists true epochCreated 518079600 geneMap geneSymbols KRAS, KRAS2, RASK2, NS, CFC2 sequenceID 8968 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance Autosomal dominant phenotype Bladder cancer, somatic phenotypeMimNumber 109800 phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance Autosomal dominant phenotype Breast cancer, somatic phenotypeMimNumber 114480 phenotypeMimNumber 615278 mimNumber 190070 phenotypeInheritance None phenotypicSeriesMimNumber 115150 phenotypeMappingKey 3 phenotype Cardiofaciocutaneous syndrome 2 phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance Autosomal dominant phenotype Gastric cancer, somatic phenotypeMimNumber 137215 phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance None phenotype Leukemia, acute myelogenous phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance Autosomal recessive phenotype Lung cancer, somatic phenotypeMimNumber 211980 phenotypeMimNumber 609942 mimNumber 190070 phenotypeInheritance None phenotypicSeriesMimNumber 163950 phenotypeMappingKey 3 phenotype Noonan syndrome 3 phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance None phenotype Pancreatic carcinoma, somatic phenotypeMimNumber 260350 phenotypeMappingKey 3 mimNumber 190070 phenotypeInheritance Somatic mosaicism phenotype SFM syndrome, somatic mosaic phenotypeMimNumber 163200 chromosomeLocationStart 25358179 chromosomeSort 213 chromosomeSymbol 12 mimNumber 190070 geneInheritance None confidence C mappingMethod REa, A, Fd geneName Kirsten rat sarcoma-2 viral (v-Ki-ras2) oncogene homolog comments pseudogene KRAS1P on 6p12-p11 mouseMgiID MGI:96680 mouseGeneSymbol Kras computedCytoLocation 12p12.1 cytoLocation 12p12.1 transcript uc001rgp.1 chromosomeLocationEnd 25403869 chromosome 12 contributors Cassandra L. Kniffin - updated : 11/12/2014 Patricia A. Hartz - updated : 5/23/2014 Ada Hamosh - updated : 12/6/2013 Ada Hamosh - updated : 7/9/2013 Ada Hamosh - updated : 7/8/2013 Cassandra L. Kniffin - updated : 1/30/2013 Cassandra L. Kniffin - updated : 7/25/2012 Ada Hamosh - updated : 7/17/2012 Cassandra L. Kniffin - updated : 6/28/2012 Marla J. F. O'Neill - updated : 11/29/2011 Cassandra L. Kniffin - updated : 2/21/2011 Ada Hamosh - updated : 2/3/2011 Ada Hamosh - updated : 8/17/2010 Ada Hamosh - updated : 3/9/2010 Ada Hamosh - updated : 12/29/2009 Cassandra L. Kniffin - updated : 10/27/2009 Ada Hamosh - updated : 10/13/2009 Marla J. F. O'Neill - updated : 6/1/2009 Cassandra L. Kniffin - updated : 3/3/2009 Ada Hamosh - updated : 1/20/2009 Ada Hamosh - updated : 7/29/2008 Cassandra L. Kniffin - updated : 3/17/2008 Ada Hamosh - updated : 11/12/2007 George E. Tiller - updated : 4/5/2007 Cassandra L. Kniffin - reorganized : 3/8/2007 Cassandra L. Kniffin - updated : 3/2/2007 Cassandra L. Kniffin - updated : 2/15/2007 Ada Hamosh - updated : 2/8/2007 Ada Hamosh - updated : 11/28/2006 Victor A. McKusick - updated : 6/13/2006 Patricia A. Hartz - updated : 4/10/2006 Patricia A. Hartz - updated : 3/28/2006 Victor A. McKusick - updated : 2/24/2006 Ada Hamosh - updated : 9/7/2005 Stylianos E. Antonarakis - updated : 3/28/2005 Marla J. F. O'Neill - updated : 3/22/2005 Victor A. McKusick - updated : 12/16/2003 John A. Phillips, III - updated : 9/2/2003 John A. Phillips, III - updated : 9/2/2003 Ada Hamosh - updated : 9/17/2002 Victor A. McKusick - updated : 8/15/2002 Victor A. McKusick - updated : 12/13/2001 Victor A. McKusick - updated : 9/26/2001 Victor A. McKusick - updated : 9/4/2001 Victor A. McKusick - updated : 8/24/2001 Ada Hamosh - updated : 4/23/2001 Ada Hamosh - updated : 4/28/2000 Ada Hamosh - updated : 2/11/2000 Paul Brennan - updated : 7/31/1998 Victor A. McKusick - updated : 3/27/1998 Paul Brennan - updated : 11/14/1997 Victor A. McKusick - edited : 3/3/1997 Mark H. Paalman - edited : 1/10/1997 externalLinks cmgGene true mgiHumanDisease false hprdIDs 01817 nbkIDs NBK1124;;Noonan Syndrome;;;NBK1186;;Cardiofaciocutaneous Syndrome refSeqAccessionIDs NG_007524.1 uniGenes Hs.505033 approvedGeneSymbols KRAS nextGxDx true locusSpecificDBs http://www.LOVD.nl/KRAS;;Mendelian genes (KRAS) flybaseIDs FBgn0003205 dermAtlas false umlsIDs C1537502,C1860979 gtr true geneIDs 3845 wormbaseIDs WBGene00062593,WBGene00092860,WBGene00028423,WBGene00164870,WBGene00002335,WBGene00122046 swissProtIDs P01116 zfinIDs ZDB-GENE-040808-67 ensemblIDs ENSG00000133703,ENST00000311936 geneTests true mgiIDs MGI:96680 ncbiReferenceSequences 530399132,575403058,575403057 genbankNucleotideSequences 123979491,190919,2881773,402830,291048721,186761,186765,29971,29973,14277199,31006019,440503002,12767837,23715,4453600,1815608,34190317,148124145,148124146,123994306,9652340,527467419,6085879,300599558,71516078,180591,511799151,576060858,511799152,190899,291048872,166706780,180593,190902,190903,158258456,190906,190907,30583144,20147726,20810304,14714718,21306554 proteinSequences 578822848,15718763,15718761,123979492,291048722,186764,4261653,440503003,15488883,131875,9652341,1335026,553519,1335027,123994307,553635,300599559,553637,576060859,291048873,180594,166706781,180592,119616917,119616919,119616918,158258457,553520,119616920,30583145,190910,20147727,190909 geneticsHomeReferenceIDs gene;;KRAS;;KRAS clinicalSynopsisExists false mimNumber 190070 allelicVariantList allelicVariant status live name LUNG CANCER, SOMATIC dbSnps rs121913530 text In a cell line of human lung cancer ({211980}), {59:Nakano et al. (1984)} identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-cys (G12C) substitution. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene. In a study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, {1:Ahrendt et al. (2001)} found that 92 (87%) were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors. mutations KRAS, GLY12CYS number 1 clinvarAccessions RCV000119791;;0;;;RCV000013406;;1;;;RCV000038265;;1 status live name LUNG CANCER, SQUAMOUS CELL, SOMATIC dbSnps rs121913530 text In a squamous cell lung carcinoma ({211980}) from a 66-year-old man, {76:Santos et al. (1984)} identified a G-to-C transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes. This mutation had previously been identified in a bladder cancer ({109800}) and a lung cancer. mutations KRAS, GLY12ARG number 2 alternativeNames BLADDER CANCER, SOMATIC, INCLUDED clinvarAccessions RCV000013407;;1;;;RCV000013408;;1 status live name BREAST ADENOCARCINOMA, SOMATIC dbSnps rs112445441 text In a cell line from a human breast adenocarcinoma ({114480}), {44:Kozma et al. (1987)} identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; {607785}), {51:Matsuda et al. (2007)} identified a somatic heterozygous G13D mutation in the KRAS gene. In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; {614470}), {85:Takagi et al. (2011)} identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. {85:Takagi et al. (2011)} noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. mutations KRAS, GLY13ASP number 3 alternativeNames JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED;; RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED clinvarAccessions RCV000144968;;0;;;RCV000038269;;1;;;RCV000013409;;1;;;RCV000144967;;0 status live name BLADDER CANCER, TRANSITIONAL CELL, SOMATIC dbSnps rs121913528 text In a human transitional cell bladder carcinoma cell line ({109800}), {28:Grimmond et al. (1992)} identified a heterozygous G-to-A transition in the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The mutation was present in paraffin-embedded tissue from the primary tumor of the patient. mutations KRAS, ALA59THR number 4 clinvarAccessions RCV000013410;;1 status live name PANCREATIC CARCINOMA, SOMATIC dbSnps rs121913529 text {57:Motojima et al. (1993)} identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas ({260350}). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; {190070.0006}), respectively. {48:Lee et al. (1995)} found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer ({137215}); 2 cases had G12D. {11:Bourdeaut et al. (2010)} found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus ({162900}) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. {29:Groesser et al. (2012)} identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see {162900}). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; {190020.0017}). The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome ({163200}) who was originally reported by {73:Rijntjes-Jacobs et al. (2010)}. {29:Groesser et al. (2012}) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. {30:Hafner et al. (2012)} identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; {607785}), {51:Matsuda et al. (2007)} identified a somatic heterozygous G12D mutation in the KRAS gene. In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; {614470}), {60:Niemela et al. (2010}) identified a somatic heterozygous G12D mutation in the KRAS gene. mutations KRAS, GLY12ASP number 5 alternativeNames GASTRIC CANCER, SOMATIC, INCLUDED;; EPIDERMAL NEVUS, SOMATIC, INCLUDED;; NEVUS SEBACEOUS, SOMATIC, INCLUDED;; SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED;; JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED;; RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED clinvarAccessions RCV000013411;;1;;;RCV000144969;;0;;;RCV000144970;;0;;;RCV000022799;;1;;;RCV000029215;;1;;;RCV000029214;;1;;;RCV000013412;;1 status live name PANCREATIC CARCINOMA, SOMATIC dbSnps rs121913529 text See {190070.0005} and {57:Motojima et al. (1993)}. {29:Groesser et al. (2012)} identified a somatic G12V mutation in 1 (2%) of 65 nevus sebaceous tumors (see {162900}). The tumor also carried a somatic mutation in the HRAS gene (G13R; {190020.0017}). mutations KRAS, GLY12VAL number 6 alternativeNames NEVUS SEBACEOUS, SOMATIC, INCLUDED clinvarAccessions RCV000013413;;1;;;RCV000029216;;1 status live name GASTRIC CANCER, SOMATIC dbSnps rs121913530 text {48:Lee et al. (1995)} found mutations in codon 12 of the KRAS2 gene in 9 of 140 cases of gastric cancer ({137215}); 7 cases had a G-to-A transition, resulting in a gly12-to-ser (G12S) substitution. In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia (JMML; {607785}), {51:Matsuda et al. (2007)} identified a somatic heterozygous G12S mutation in the KRAS gene. mutations KRAS, GLY12SER number 7 alternativeNames JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED clinvarAccessions RCV000038264;;1;;;RCV000144971;;0;;;RCV000013414;;1;;;RCV000119790;;0 status live name LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC text In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; {601626}), {10:Bollag et al. (1996)} identified an in-frame 3-bp insertion in exon 1 of the KRAS2 gene, resulting in an insertion of gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels measured in COS cells established that this novel mutant accumulates up to 90% in the GTP state, considerably higher than a residue 12 mutant. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or 61. mutations KRAS, 3-BP INS, GLY11INS number 8 clinvarAccessions RCV000013415;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs104894359 text In an individual with CFC syndrome (CFC2; {615278}), {61:Niihori et al. (2006)} identified a heterozygous 178G-C transversion in exon 2 of the KRAS2 gene, predicting a gly60-to-arg (G60R) substitution. mutations KRAS, GLY60ARG number 9 clinvarAccessions RCV000013416;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs104894360 text In 2 unrelated individuals with CFC syndrome (CFC2; {615278}), {61:Niihori et al. (2006)} identified a heterozygous 458A-T transversion in exon 4b of the KRAS2 gene, predicting an asp153-to-val (D153V) substitution. The D153V mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R ({190070.0009}) were not found in 100 control chromosomes and were not found in any parent. The results suggested that these germline mutations occurred de novo. {77:Schubbert et al. (2006)} found the D153V mutation in a patient who had been diagnosed with Noonan syndrome-3 ({609942}). The 18-year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures. mutations KRAS, ASP153VAL number 10 alternativeNames NOONAN SYNDROME 3, INCLUDED clinvarAccessions RCV000013418;;1;;;RCV000013417;;1 status live name NOONAN SYNDROME 3 dbSnps rs104894364 text In a 3-month-old female with Noonan syndrome-3 ({609942}), {77:Schubbert et al. (2006)} identified a heterozygous 173C-T transition in the KRAS2 gene, resulting in a thr58-to-ile (T58I) substitution. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia (JMML; {607785}) type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis. {46:Kratz et al. (2009)} identified a de novo heterozygous T58I mutation in a patient with Noonan syndrome who also had craniosynostosis, suggesting a genotype/phenotype correlation. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. mutations KRAS, THR58ILE number 11 clinvarAccessions RCV000013419;;1 status live name NOONAN SYNDROME 3 dbSnps rs104894365 text In 3 of 124 unrelated individuals with Noonan syndrome-3 ({609942}) without mutations in PTPN11 ({176876}), {77:Schubbert et al. (2006)} identified a heterozygous 40G-A transition in the KRAS2 gene, resulting in a val14-to-ile (V14I) substitution. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. mutations KRAS, VAL14ILE number 12 clinvarAccessions RCV000119792;;0;;;RCV000013420;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs104894366 text In a 13-year-old female with the diagnosis of cardiofaciocutaneous syndrome (CFC2; {615278}), {77:Schubbert et al. (2006)} found a heterozygous pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum. mutations KRAS, PRO34ARG number 13 clinvarAccessions RCV000013421;;1;;;RCV000043674;;1 status live name NOONAN SYNDROME 3 dbSnps rs104894367 text In a 1-year-old girl with the diagnosis of Noonan syndrome-3 ({609942}), {15:Carta et al. (2006)} identified a 455T-G transversion in the KRAS2 gene, resulting in a val152-to-gly (V152G) substitution. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia. She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome ({218040}) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive) and, to a lesser extent, CFC syndrome ({115150}) (macrocephaly and sparse hair). mutations KRAS, VAL152GLY number 14 clinvarAccessions RCV000013422;;1 status live name NOONAN SYNDROME 3 text In a 14-year-old girl with Noonan syndrome-3 ({609942}) and some features of CFC syndrome ({115150}), {15:Carta et al. (2006)} identified a 458A-T transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V) substitution. The girl had short stature and growth retardation and delayed bone age, cardiac defects (moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect), dysmorphic features (hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge), short and mildly webbed neck, wide-set nipples, and developmental delay. There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios. mutations KRAS, ASP153VAL number 15 clinvarAccessions RCV000013417;;1;;;RCV000013418;;1 status live name PILOCYTIC ASTROCYTOMA, SOMATIC dbSnps rs121913535 text In 1 of 21 sporadic pilocytic astrocytoma (PA) (see {137800}) samples, {79:Sharma et al. (2005)} identified a G-to-C transversion in the KRAS2 gene, resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the cortex of an 11-year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT (see {164730}) activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway. No mutations in the KRAS gene were observed in the other tumors, and none of the 21 tumors showed mutations in the HRAS ({190020}) or NRAS ({164790}) genes. Of note, the G13R substitution occurs in the same codon as another KRAS mutation (G13D; {190070.0003}) identified in a breast carcinoma cell line. mutations KRAS, GLY13ARG number 16 clinvarAccessions RCV000013424;;1;;;RCV000038267;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs104894361 text In a 7.5-month-old male infant with a clinical diagnosis of Costello syndrome ({218040}), {95:Zenker et al. (2007)} identified a heterozygous 15A-T transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn (K5N) substitution. The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. {95:Zenker et al. (2007)} noted that the patient may later develop features of CFC (CFC2; {615278}), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. {42:Kerr et al. (2008)} commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene ({190020}). mutations KRAS, LYS5ASN number 17 clinvarAccessions RCV000013425;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs104894362 text In a male infant with a clinical diagnosis of Costello syndrome ({218040}) who died suddenly at age 14 months, {95:Zenker et al. (2007)} identified a heterozygous 468C-G transversion in the KRAS2 gene, resulting in a phe156-to-leu (F156L) substitution. The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. {95:Zenker et al. (2007)} noted that the patient may later develop features of CFC (CFC2; {615278}), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. {42:Kerr et al. (2008)} commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene ({190020}). mutations KRAS, PHE156LEU number 18 clinvarAccessions RCV000013426;;1 status live name NOONAN SYNDROME 3 dbSnps rs193929331 text In a 20-year-old woman with clinical features typical of Costello syndrome ({218040}) and additional findings seen in Noonan syndrome ({609942}), {6:Bertola et al. (2007)} identified a 194A-G transition in exon 2 of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The mutation was not found in her unaffected mother or brother or in 100 controls. {42:Kerr et al. (2008)} commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene ({190020}). {7:Bertola et al. (2012)} reported a patient with a germline K5E mutation and dysmorphic features who developed multiple diffuse schwannomas. mutations KRAS, LYS5GLU number 19 clinvarAccessions RCV000013427;;1 status live name NOONAN SYNDROME 3 dbSnps rs104894359 text In a patient with Noonan syndrome-3 ({609942}) and craniosynostosis, {46:Kratz et al. (2009)} identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. A mutation in this same codon (G60R; {190070.0009}) has been found in a patient with cardiofaciocutaneous syndrome ({115150}). mutations KRAS, GLY60SER number 20 clinvarAccessions RCV000013428;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs387907205 text In a mother and son with variable features of cardiofaciocutaneous syndrome (CFC2; {615278}), {84:Stark et al. (2012)} identified a heterozygous 211T-C transition in exon 3 of the KRAS gene, resulting in a tyr71-to-his (Y71H) substitution in a highly conserved residue close to a region that is important for effector and regulator binding. The mutation was not found in 500 control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 ({601097}) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation. Y71 is located at the end of the switch II region of KRAS. Using in vitro assays and transfected COS-7 cells, {18:Cirstea et al. (2013)} found that the Y71H mutation increased the binding affinity of KRAS for its major effector, RAF1 kinase ({164760}), leading to increased activation of MEK1 ({176872})/MEK2 ({601263}) and ERK1 ({601795})/ERK2 ({176948}), irrespective of stimulation. The mutation did not alter the rate of nucleotide dissociation by KRAS. mutations KRAS, TYR71HIS number 21 clinvarAccessions RCV000024617;;1 status live name CARDIOFACIOCUTANEOUS SYNDROME 2 dbSnps rs387907206 text In a girl with variable features of CFC (CFC2; {615278}), {84:Stark et al. (2012)} identified a de novo heterozygous 439A-G transition in exon 4 of the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a highly conserved residue close to known mutations. Lys147 is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. In vitro studies demonstrated that the K147E mutant protein predominates in the active GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP exchange. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development. K147 is a conserved amino acid within a motif required for guanine base binding by KRAS. K147 is also ubiquitinated, leading to increased KRAS activation by GEF proteins. Using in vitro assays and transfected COS-7 cells, {18:Cirstea et al. (2013)} found that the K147E mutation significantly increased nucleotide dissociation in KRAS, generating a self-activating protein that acted independently of upstream signaling. However, overactivity of K147E mutant KRAS was subject to normal downregulation by RasGAP (see {139150}) and had 2-fold lower affinity for RAF1 kinase ({164760}). mutations KRAS, LYS147GLU number 22 clinvarAccessions RCV000024618;;1 status live name RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC dbSnps rs121913535 text In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; {614470}), {60:Niemela et al. (2010}) identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function. mutations KRAS, GLY13CYS number 23 clinvarAccessions RCV000038268;;1;;;RCV000144972;;0 prefix * titles alternativeTitles ONCOGENE KRAS2; KRAS2;; KIRSTEN MURINE SARCOMA VIRUS 2; RASK2;; C-KRAS includedTitles V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED;; ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED;; KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED preferredTitle V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG; KRAS textSectionList textSection textSectionTitle Description textSectionContent The KRAS gene encodes the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers. The most well-studied members of the RAS (derived from 'RAt Sarcoma' virus) gene family include KRAS, HRAS ({190020}), and NRAS ({164790}). These genes encode immunologically related proteins with a molecular mass of 21 kD and are homologs of rodent sarcoma virus genes that have transforming abilities. While these wildtype cellular proteins in humans play a vital role in normal tissue signaling, including proliferation, differentiation, and senescence, mutated genes are potent oncogenes that play a role in many human cancers ({90:Weinberg, 1982}; {45:Kranenburg, 2005}). textSectionName description textSectionTitle Cloning textSectionContent {23:Der et al. (1982)} identified a new human DNA sequence homologous to the transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated human lung cancer cell line (LX-1). The findings showed that KRAS could act as an oncogene in human cancer. {17:Chang et al. (1982)} isolated clones corresponding to the human cellular KRAS gene from human placental and embryonic cDNA libraries. Two isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained 0.9 kb homologous to viral Kras and had 1 intervening sequence, and KRAS2 contained 0.3 kb homologous to viral Kras. {53:McCoy et al. (1983)} characterized the KRAS gene isolated from a human colon adenocarcinoma cell line (SW840) and determined that it corresponded to KRAS2 as identified by {17:Chang et al. (1982)}. The KRAS2 oncogene was amplified in several tumor cell lines. {54:McGrath et al. (1983)} cloned the KRAS1 and KRAS2 genes and determined that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a 188-residue protein with a molecular mass of 21.66 kD. It showed only 6 amino acid differences from the viral gene. Comparison of the 2 KRAS genes showed that KRAS1 is lacking several intervening sequences, consistent with it being a pseudogene derived from a processed KRAS2 mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing results in 2 variants, isoforms A and B, that differ in the C-terminal region. Alternative splicing of exon 5 results in the KRASA and KRASB isoforms. Exon 6 contains the C-terminal region in KRASB, whereas it encodes the 3-prime untranslated region in KRASA. The differing C-terminal regions of these isoforms are subjected to posttranslational modifications. The differential posttranslational processing has profound functional effects leading to alternative trafficking pathways and protein localization ({15:Carta et al., 2006}). textSectionName cloning textSectionTitle Gene Structure textSectionContent {54:McGrath et al. (1983)} first reported that the KRAS2 gene spans 38 kb and contains 4 exons. Detailed sequence analysis showed that exon 4 has 2 forms, which the authors designated 4A and 4B. The KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6 encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes the C-terminal region ({15:Carta et al., 2006}). textSectionName geneStructure textSectionTitle Mapping textSectionContent By in situ hybridization, {69:Popescu et al. (1985)} mapped the KRAS2 gene to chromosome 12p12.1-p11.1. By linkage with RFLPs, {64:O'Connell et al. (1985)} confirmed the approximate location of KRAS2 on 12p12.1. Pseudogene The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome 6 ({63:O'Brien et al., 1983}; {52:McBride et al., 1983}). By in situ hybridization, {69:Popescu et al. (1985)} assigned the KRAS1 gene to 6p12-p11. Because KRAS1 was found to be a pseudogene, its official symbol was changed to KRAS1P. textSectionName mapping textSectionTitle Gene Function textSectionContent {40:Johnson et al. (2005)} found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 ({605386}) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer. {9:Bivona et al. (2006)} found that the subcellular localization and function of Kras in mammalian cells was modulated by Pkc (see {176960}). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; {600039}). Phosphorylated Kras required Bclxl for induction of apoptosis. {93:Yeung et al. (2006)} devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS, RAC1 ({602048}), and c-SRC ({190090}) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis. {33:Heo et al. (2006)} surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, {33:Heo et al. (2006)} developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting. {27:Gazin et al. (2007)} performed a genomewide RNA interference (RNAi) screen in KRAS-transformed NIH 3T3 cells and identified 28 genes required for RAS-mediated epigenetic silencing of the proapoptotic FAS gene (TNFRSF6; {134637}). At least 9 of these RAS epigenetic silencing effectors (RESEs), including the DNA methyltransferase DNMT1 ({126375}), were directly associated with specific regions of the FAS promoter in KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit DNMT1 to the FAS promoter, loss of FAS promoter hypermethylation, and derepression of FAS expression. Analysis of 5 other epigenetically repressed genes indicated that RAS directs the silencing of multiple unrelated genes through a largely common pathway. Finally, {27:Gazin et al. (2007)} showed that 9 RESEs are required for anchorage-independent growth and tumorigenicity of KRAS-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by RAS. {27:Gazin et al. (2007)} concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype. {31:Haigis et al. (2008)} used genetically engineered mice to determine whether and how the related oncogenes Kras and Nras ({164790}) regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see {176872})-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc ({611731})-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see {164760}) but not Mek. {31:Haigis et al. (2008)} concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways. By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF ({164757}) genes, {94:Yun et al. (2009)} found that GLUT1 ({138140}), encoding glucose transporter-1, was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. {94:Yun et al. (2009)} concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors. {55:Meylan et al. (2009)} showed that the NF-kappa-B (see {164011}) pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 ({191170}) and expression of oncogenic Kras containing the G12D mutation resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. {55:Meylan et al. (2009)} concluded that, together, their results indicated a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status. {5:Barbie et al. (2009)} used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 ({604834}) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL ({164910}) and BCLXL (BCL2L1; {600039}) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. {5:Barbie et al. (2009)} concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and establish a general approach for the rational identification of codependent pathways in cancer. In Drosophila eye-antennal discs, cooperation between Ras(V12), an oncogenic form of the Ras85D protein, and loss-of-function mutations in the conserved tumor suppressor 'scribble' ({607733}) gives rise to metastatic tumors that display many characteristics observed in human cancers (summary by {91:Wu et al., 2010}). {91:Wu et al. (2010)} showed that clones of cells bearing different mutations can cooperate to promote tumor growth and invasion in Drosophila. The authors found that the Ras(V12) and scrib-null mutations can also cause tumors when they affect different adjacent epithelial cells. {91:Wu et al. (2010)} showed that this interaction between Ras(V12) and scrib-null clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines (see {604260}), a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumors can also be triggered by tissue damage, a stress condition that activates JNK signaling. The authors suggested that similar cooperative mechanisms could have a role in the development of human cancers. Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDE-delta (PDED; {602676}), which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm ({16:Chandra et al., 2012}; {96:Zhang et al., 2004}). {98:Zimmerman et al. (2013)} reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Regulation of KRAS Expression by KRAS1P Transcript Levels Following their finding that PTENP1 ({613531}), a pseudogene of the PTEN ({601728}) tumor suppressor gene, can derepress PTEN by acting as a decoy for PTEN-targeting miRNAS, {68:Poliseno et al. (2010)} extended their analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime UTR overexpression in DU145 prostate cancer cells resulted in increased KRAS mRNA abundance and accelerated cell growth. They also found that KRAS and KRAS1P transcript levels were positively correlated in prostate cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different human tumors, including neuroblastoma, retinoblastoma, and hepatocellular carcinoma. {68:Poliseno et al. (2010)} concluded that their findings together pointed to a putative protooncogenic role for KRAS1P, and supported the notion that pseudogene functions mirror the functions of their cognate genes as explained by a miRNA decoy mechanism. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Role in Solid Tumors KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation ({45:Kranenburg, 2005}). Critical regions of the KRAS gene for oncogenic activation include codons 12, 13, 59, 61, and 63 ({28:Grimmond et al., 1992}). These activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase activating proteins ({95:Zenker et al., 2007}). In a study of 96 human tumors or tumor cell lines in the NIH 3T3 transforming system, {71:Pulciani et al. (1982)} found a mutated HRAS locus only in a single cancer cell line, whereas transforming KRAS genes were identified in 8 different carcinomas and sarcomas. KRAS appeared to be involved in malignancy much more often than HRAS. In a serous cystadenocarcinoma of the ovary ({167000}), {26:Feig et al. (1984)} showed the presence of an activated KRAS oncogene that was not activated in normal cells of the same patient. The transforming gene product displayed an electrophoretic mobility pattern that differed from that of KRAS transforming proteins in other tumors, suggesting a novel somatic KRAS mutation in this tumor. In a cell line of human lung cancer ({211980}), {59:Nakano et al. (1984)} identified a mutation in the KRAS2 gene ({190070.0001}), resulting in gene activation with transforming ability of the mutant protein. {74:Rodenhuis et al. (1987)} used a novel, highly sensitive assay based on oligonucleotide hybridization following in vitro amplification to examine DNA from 39 lung tumor specimens. The KRAS gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small cell carcinoma. An approximately 20-fold amplification of the unmutated KRAS gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. {92:Yanez et al. (1987)} found mutations in codon 12 of the KRAS gene in 4 of 16 colon cancers ({114500}), 2 of 27 lung cancers, and 1 of 8 breast cancers ({114480}); no mutations were found at codon position 61. The highest observed frequency of KRAS2 point mutations occurs in pancreatic carcinomas ({260350}), with 90% of the patients having at least 1 KRAS2 mutation ({2:Almoguera et al., 1988}; {82:Smit et al., 1988}). Most of these mutations are in codon 12 (see, e.g., G12D, {190070.0005} and G12V, {190070.0006}) ({36:Hruban et al., 1993}). {12:Burmer and Loeb (1989)} identified KRAS2 mutations in both diploid and aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon carcinomas contained mutations at codon 12, and 9 of the 12 adenomas studied contained similar mutations. {81:Sidransky et al. (1992)} found that KRAS mutations were detectable in DNA purified from stool in 8 of 9 patients with colorectal tumors that contained KRAS mutations. {86:Takeda et al. (1993)} used a mutant-allele-specific amplification (MASA) method to detect KRAS mutations in cells obtained from the sputum of patients with lung cancer. A mutation was found in 1 of 5 patients studied. The authors suggested that the MASA system could be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas of the colon and pancreas in which KRAS mutations are frequently detected, and to mass screening for colorectal tumors, using DNA isolated from feces as a template. {48:Lee et al. (1995)} identified mutations in codon 12 of the KRAS gene in 11 (7.9%) of 140 gastric cancers ({137215}). Seven cases had a G12S mutation ({190070.0007}) and 2 had a G12D mutation ({190070.0005}). Tumors located in the upper third of the stomach had a significantly higher frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%) thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer located in the upper part of the stomach, death occurred in 4 of 5 patients with tumors without KRAS gene mutations, but in none of the 3 patients with KRAS gene-mutated tumors. {66:Otori et al. (1997)} examined tissue sections from 19 hyperplastic colorectal polyps for mutations in exons 12 and 13 of the KRAS gene. KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that some hyperplastic colorectal polyps may be true premalignant lesions. KRAS activation has been recognized in microdissected foci of pancreatic intraepithelial neoplasia ({21:Cubilla and Fitzgerald, 1976}; {35:Hruban et al., 2000}; {37:Hruban et al., 2000}), the candidate precursor lesion of pancreatic cancer previously known as ductal cell hyperplasia. {47:Laghi et al. (2002)} found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS mutations were found in 16 pancreatic cancers and in 8 biliary cancers. Multiple KRAS mutations were more frequent in cancers with detectable pancreatic intraepithelial neoplasia than in those without, and individual precursor lesions of the same neoplastic pancreas harbored distinct mutations. The results indicated that clonally distinct precursor lesions of pancreatic cancer may variably contribute to tumor development. {62:Nikiforova et al. (2003)} analyzed a series of 88 conventional follicular ({188470}) and Hurthle cell ({607464}) thyroid tumors for HRAS, NRAS, or KRAS mutations and PAX8 ({167415})-PPARG ({601487}) rearrangements. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations. {72:Rajagopalan et al. (2002)} systematically evaluated mutations in the BRAF ({164757}) and KRAS genes in 330 colorectal tumors. There were 32 mutations in BRAF and 169 mutations in KRAS; no tumor exhibited mutations in both BRAF and KRAS. {72:Rajagopalan et al. (2002)} concluded that BRAF and KRAS mutations are equivalent in their tumorigenic effects and are mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. {43:Kim et al. (2003)} found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found. {65:Oliveira et al. (2004)} investigated KRAS in 158 hereditary nonpolyposis colorectal cancer (HNPCC2; {609310}) tumors from patients with germline MLH1 ({120436}), MSH2 ({609309}) or MSH6 ({600678}) mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D ({190070.0003}) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. The authors concluded that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status) and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway. {83:Sommerer et al. (2005)} analyzed the KRAS gene in 30 seminomas and 32 nonseminomatous GCTs (see {273300}) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas. {29:Groesser et al. (2012)} identified somatic mutations in the KRAS gene (G12D, {190070.0005} and G12V, {190070.0006}) in 3 (5%) of 65 nevus sebaceous tumors (see {162900}). The G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome ({163200}). The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in the latter disorder, which could explain the phenotypic pleiotropy. {89:Vermeulen et al. (2013)} quantified the competitive advantage in tumor development of Apc ({611731}) loss, Kras activation, and p53 ({191170}) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, {89:Vermeulen et al. (2013)} found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. {89:Vermeulen et al. (2013)} concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages. Hematologic Malignancies The myelodysplastic syndrome is a preleukemic hematologic disorder characterized by low blood counts, bone marrow cells of abnormal appearance, and progression to acute leukemia in as many as 30% of patients. {49:Liu et al. (1987)} identified a transforming allele in the KRAS gene in 2 of 4 patients with preleukemia and in 1 who progressed to acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient, they detected a novel mutation in codon 13 of KRAS in bone marrow cells harvested 1.5 years before the acute leukemia developed. The findings provided evidence that RAS mutations may be involved in the early stages of human leukemia. In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; {601626}), {10:Bollag et al. (1996)} identified a somatic in-frame 3-bp insertion in the KRAS gene ({190070.0008}). {8:Bezieau et al. (2001)} used ARMS (allele-specific amplification method) to evaluate the incidence of NRAS- and KRAS2-activating mutations in patients with multiple myeloma ({254500}) and related disorders. Mutations were more frequent in KRAS2 than in NRAS. The authors concluded that early mutations in these 2 oncogenes may play a major role in the oncogenesis of multiple myeloma and primary plasma cell leukemia. In white blood cells derived from 3 unrelated girls with juvenile myelomonocytic leukemia (JMML; {607785}), {51:Matsuda et al. (2007)} identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, {190070.0003}; G12D, {190070.0005}; and G12S, {190070.0007}). The patients were ascertained from a cohort of 80 children with JMML. The {13:Cancer Genome Atlas Research Network (2013)} analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The {13:Cancer Genome Atlas Research Network (2013)} identified recurrent mutations in the NRAS ({164790}) or KRAS genes in 23/200 (12%) samples. RAS-Associated Autoimmune Leukoproliferative Disorder In 2 unrelated girls with RAS-associated autoimmune leukoproliferative disorder (RALD; {614470}), {60:Niemela et al. (2010)} identified different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, {190070.0005} and G13C, {190070.0023}). The patients presented in early childhood with lymphadenopathy, splenomegaly, and autoimmune disorders. One patient had recurrent infections. In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapototic protein BIM (BCL2L11; {603827}) and facilitated lymphocyte proliferation through downregulation of CDKN1B ({600778}). Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello Syndrome Cardiofaciocutaneous (CFC) syndrome (see {115150}) is characterized by distinctive facial appearance, heart defects, and mental retardation. CFC shows phenotypic overlap with Noonan syndrome (see {163950}) and Costello syndrome ({218040}). Approximately 40% of individuals with clinically diagnosed Noonan syndrome have gain-of-function mutations in protein-tyrosine phosphatase SHP2 (PTPN11; {176876}). {4:Aoki et al. (2005)} identified mutations in the HRAS gene in 12 of 13 individuals with Costello syndrome, suggesting that the activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome, Costello syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals with CFC syndrome (CFC2; {615278}), {61:Niihori et al. (2006)} identified different heterozygous KRAS mutations (G60R, {190070.0009} and D153V, {190070.0010}). Neither mutation had previously been identified in individuals with cancer. In the same study, {61:Niihori et al. (2006)} found 8 different mutations in the BRAF gene ({164757}), an isoform in the RAF protooncogene family, in 16 of 40 individuals with CFC syndrome. {77:Schubbert et al. (2006)} identified 3 de novo germline KRAS mutations ({190070.0010}-{190070.0012}) in 5 individuals with Noonan syndrome-3 (NS3; {609942}). In 2 individuals exhibiting a severe Noonan syndrome-3 phenotype with features overlapping those of CFC and Costello syndromes, {15:Carta et al. (2006)} identified 2 different heterozygous KRAS mutations ({190070.0014} and {190070.0015}). Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor. {95:Zenker et al. (2007)} identified 11 different germline mutations in the KRAS gene, including 8 novel mutations, in a total of 12 patients with a clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan syndrome overlap (1), or Costello syndrome (2). All patients showed mild to moderate mental retardation. The 2 unrelated infants with Costello syndrome had 2 different heterozygous mutations ({190070.0017}-{190070.0018}). Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. {95:Zenker et al. (2007)} noted that these patients may later develop features of CFC syndrome, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these diverse but phenotypically related disorders. In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, {6:Bertola et al. (2007)} identified a mutation in the KRAS gene (K5E; {190070.0019}). The authors noted that this mutation was in the same codon as that of 1 of the patients reported by {95:Zenker et al. (2007)} (K5N; {190070.0017}). {78:Schulz et al. (2008)} identified mutations in the KRAS gene in 3 (5.9%) of 51 CFC patients. Development of Resistance to Chemotherapeutic Agents {56:Misale et al. (2012)} showed that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR ({131550}) treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. {56:Misale et al. (2012)} concluded that their results identified KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicated that the emergence of KRAS mutant clones can be detected noninvasively months before radiographic progression, and suggested early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. {24:Diaz et al. (2012)} determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of 24 (38%) patients whose tumors were initially KRAS wildtype developed detectable mutations in KRAS in their sera, 3 of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. {24:Diaz et al. (2012)} suggested that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a noninvasive manner. The results also explained why solid tumors develop resistance to targeted therapies in a highly reproducible fashion. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent {3:Andreyev et al. (1997)} used PCR amplification and DNA sequencing to investigate KRAS exon 1 mutations (codons 12 and 13) in histologic sections of colorectal adenocarcinomas. They examined samples from 98 patients with Dukes stage A or B fully resected colorectal cancers. Fourteen of these patients had subsequently relapsed. The presence of a KRAS mutation was not associated with tumor stage or histologic grade; neither was there any association with those patients who relapsed. The authors concluded that detection of KRAS mutation in early colorectal adenocarcinomas was of no prognostic value. {70:Porta et al. (1999)} found that serum concentrations of organochlorine compounds were significantly higher in patients with exocrine pancreatic cancer with a codon 12 KRAS2 mutation compared to cases without a mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for another organochlorine. These estimates held after adjusting for total lipids, other covariates, and total polychlorinated biphenyls (PCBs). A specific association was observed between the G12V ({190070.0006}) mutation and both organochlorine concentrations, with an odds ratio of 15.9 and 24.1 for each of the compounds. A similar pattern was shown for the major diorthochlorinated PCBs. {88:Vasko et al. (2003)} performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid tumors. Mutations in codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary tumors ({188550}) (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of the study by {88:Vasko et al. (2003)} involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and in 1 follicular carcinoma (2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. textSectionName genotypePhenotypeCorrelations textSectionTitle Population Genetics textSectionContent Although several studies confirmed that approximately 40% of primary colorectal adenocarcinomas in humans contain a mutated form of the KRAS2 gene, the patterns of mutation at codons 12, 13, and 61 are not the same in different populations. {32:Hayashi et al. (1996)} used the MASA method to analyze the frequency and type of point mutations in these 3 codons in 319 colorectal cancer tissues collected from patients in Japan. They then compared these results with those from other sources to examine whether different geographic locations and environmental influences might impose distinct patterns on the spectrum of KRAS mutations. Comparing findings in the U.S., France, and Yugoslavia with those in Japan, a number of significant differences were found. A possible explanation put forth by {32:Hayashi et al. (1996)} was that an environmental carcinogen prevailing in a geographic region combines with the susceptibility of a particular tissue to dictate which type of DNA lesion will predominate. The predominance of G-to-A mutations among American and Japanese colorectal cancer patients could be attributable to alkylating agents or to the absence of direct interaction with any carcinogens. The prevalence of G-to-T mutations among Yugoslav and French patients might be ascribed to polycyclic aromatic hydrocarbons and heterocyclic amines. textSectionName populationGenetics textSectionTitle Animal Model textSectionContent {58:Muller et al. (1983)} found transcription of KRAS and the McDonough strain of feline sarcoma virus (FMS) gene (see {164770}) during mouse development. Furthermore, the differences in transcription in different tissues suggested a specific role for each: FMS was expressed in extraembryonic structures or in transport in these tissues, whereas KRAS was expressed ubiquitously. {34:Holland et al. (2000)} transferred, in a tissue-specific manner, genes encoding activated forms of Ras and Akt ({164730}) to astrocytes and neural progenitors in mice. Although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; {137800}) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and {34:Holland et al. (2000)} demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease. {39:Johnson et al. (2001)} used a variation of 'hit-and-run' gene targeting to create mouse strains carrying oncogenic alleles of Kras capable of activation only on a spontaneous recombination event in the whole animal. They demonstrated that mice carrying these mutations were highly predisposed to a range of tumor types, predominantly early-onset lung cancer. This model was further characterized by examining the effects of germline mutations in the p53 gene ({191170}), which is known to be mutated along with KRAS in human tumors. {39:Johnson et al. (2001)} concluded that their approach had several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers. {97:Zhang et al. (2001)} presented evidence of a tumor suppressor role of wildtype KRAS2 in lung tumorigenesis. They found that heterozygous Kras2-deficient mice were highly susceptible to the chemical induction of lung tumors compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of chemically induced mouse lung adenocarcinomas that harbored a mutant Kras2 allele. These and other data strongly suggested that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. {67:Pfeifer (2001)} commented on these findings as representing 'a new verdict for an old convict.' He quoted evidence that the HRAS1 gene may also function as a tumor suppressor. {67:Pfeifer (2001)} noted an interesting parallel to the p53 tumor suppressor, which was initially described as an oncogene, carrying point mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation. {20:Costa et al. (2002)} crossed Nf1 ({613113}) heterozygote mice with mice heterozygous for a null mutation in the Kras gene. Double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. {20:Costa et al. (2002)} also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. {20:Costa et al. (2002)} concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. An S17N substitution in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, {50:Matallanas et al. (2003)} found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts. By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, {25:Dinulescu et al. (2005)} expressed an oncogenic Kras allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma ({167000}); 7 of 15 mice (47%) also developed peritoneal endometriosis ({131200}). When the Kras mutation was combined with conditional deletion of Pten ({601728}), all mice developed invasive endometrioid ovarian adenocarcinomas. {25:Dinulescu et al. (2005)} stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. {19:Collado et al. (2005)} used a mouse model for cancer initiation in humans: the animals had a conditional oncogenic K-rasV12 ({190070.0006}) allele that is activated only by the enzyme Cre recombinase, causing them to develop multiple lung adenomas (premalignant tumors) and a few lung adenocarcinomas (malignant tumors). Senescence markers previously identified in cultured cells were used to detect oncogene-induced senescence in lung sections from control mice (expressing Cre) and from K-rasV12-expressing mice (expressing Cre and activated K-rasV12). {19:Collado et al. (2005)} analyzed p16(INK4a) ({600160}), an effector of in vitro oncogene-induced senescence, and de novo markers that were identified by using DNA microarray analysis of in vitro oncogene-induced senescence. These de novo markers are p15(INK4b), also known as CDKN2B ({600431}), DEC1 (BHLHB2; {604256}), and DCR2 (TNFRSF10D; {603614}). Staining with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed abundant positive cells in adenomas, whereas adenocarcinomas were essentially negative. By contrast, the proliferation marker Ki-67 revealed a weak proliferative index in adenomas compared with adenocarcinomas. {19:Collado et al. (2005)} concluded that oncogene-induced senescence may help to restrict tumor progression. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16(INK4a) or p53. Using an Hras ({190020}) knockin mouse model, {87:To et al. (2008)} demonstrated that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. {87:To et al. (2008)} concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers. {41:Junttila et al. (2010)} modeled the probable therapeutic impact of p53 ({191170}) restoration in a spontaneously evolving mouse model of nonsmall cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of endogenous KRAS developed by {38:Jackson et al. (2001)}. Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19(ARF) ({600160}). {41:Junttila et al. (2010)} concluded that p53-mediated tumor suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers. textSectionName animalModel geneMapExists true editHistory carol : 11/18/2014 mcolton : 11/13/2014 ckniffin : 11/12/2014 mgross : 5/23/2014 mgross : 5/23/2014 mcolton : 5/22/2014 mcolton : 5/22/2014 alopez : 12/6/2013 alopez : 7/9/2013 alopez : 7/9/2013 alopez : 7/8/2013 alopez : 6/20/2013 alopez : 2/6/2013 ckniffin : 1/30/2013 carol : 7/26/2012 carol : 7/26/2012 carol : 7/25/2012 ckniffin : 7/25/2012 alopez : 7/19/2012 terry : 7/17/2012 terry : 7/3/2012 carol : 7/2/2012 ckniffin : 6/28/2012 terry : 4/9/2012 alopez : 3/7/2012 carol : 12/8/2011 carol : 11/29/2011 terry : 3/10/2011 wwang : 3/1/2011 ckniffin : 2/21/2011 alopez : 2/7/2011 alopez : 2/7/2011 alopez : 2/7/2011 alopez : 2/7/2011 terry : 2/3/2011 terry : 11/3/2010 alopez : 8/20/2010 terry : 8/17/2010 alopez : 3/9/2010 terry : 3/9/2010 alopez : 1/6/2010 terry : 12/29/2009 carol : 11/23/2009 carol : 11/23/2009 wwang : 11/6/2009 ckniffin : 10/27/2009 alopez : 10/23/2009 terry : 10/13/2009 joanna : 9/14/2009 wwang : 6/3/2009 terry : 6/1/2009 wwang : 3/5/2009 ckniffin : 3/3/2009 alopez : 2/6/2009 carol : 2/6/2009 terry : 1/20/2009 alopez : 7/31/2008 terry : 7/29/2008 wwang : 3/19/2008 ckniffin : 3/17/2008 alopez : 11/14/2007 alopez : 11/14/2007 terry : 11/12/2007 carol : 9/10/2007 carol : 9/6/2007 alopez : 4/13/2007 terry : 4/5/2007 carol : 3/8/2007 carol : 3/8/2007 ckniffin : 3/8/2007 ckniffin : 3/2/2007 wwang : 2/19/2007 ckniffin : 2/15/2007 alopez : 2/8/2007 alopez : 2/8/2007 alopez : 2/8/2007 terry : 2/1/2007 alopez : 12/7/2006 terry : 11/28/2006 alopez : 6/16/2006 terry : 6/13/2006 mgross : 4/14/2006 terry : 4/10/2006 wwang : 3/30/2006 terry : 3/28/2006 alopez : 3/3/2006 terry : 2/24/2006 alopez : 9/14/2005 terry : 9/7/2005 alopez : 7/14/2005 carol : 5/27/2005 mgross : 3/28/2005 tkritzer : 3/22/2005 tkritzer : 12/16/2003 cwells : 11/6/2003 alopez : 9/2/2003 alopez : 9/2/2003 terry : 1/2/2003 terry : 11/22/2002 alopez : 9/17/2002 tkritzer : 8/21/2002 tkritzer : 8/19/2002 terry : 8/15/2002 terry : 3/5/2002 alopez : 2/5/2002 alopez : 1/22/2002 carol : 1/3/2002 mcapotos : 12/19/2001 terry : 12/13/2001 carol : 10/4/2001 mcapotos : 10/3/2001 terry : 9/26/2001 alopez : 9/4/2001 alopez : 8/27/2001 terry : 8/24/2001 alopez : 4/25/2001 terry : 4/23/2001 alopez : 5/1/2000 terry : 4/28/2000 alopez : 2/15/2000 terry : 2/11/2000 mgross : 6/22/1999 alopez : 9/22/1998 alopez : 9/22/1998 terry : 7/24/1998 dkim : 7/23/1998 psherman : 3/27/1998 dholmes : 3/6/1998 alopez : 11/26/1997 alopez : 11/26/1997 alopez : 11/17/1997 alopez : 11/17/1997 alopez : 11/17/1997 alopez : 11/14/1997 mark : 3/3/1997 mark : 1/10/1997 mark : 1/10/1997 terry : 11/6/1996 terry : 10/31/1996 mark : 8/10/1995 mimadm : 6/7/1995 carol : 11/1/1993 carol : 6/30/1993 carol : 6/22/1993 carol : 6/7/1993 dateCreated Mon, 02 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/2/1986 epochUpdated 1416297600 dateUpdated Tue, 18 Nov 2014 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1002/1097-0142(20010915)92:6<1525::AID-CNCR1478>3.0.CO;2-H publisherName John Wiley & Sons, Inc. title Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. mimNumber 190070 referenceNumber 1 publisherAbbreviation Wiley pubmedID 11745231 source Cancer 92: 1525-1530, 2001. authors Ahrendt, S. A., Decker, P. A., Alawi, E. A., Zhu, Y., Sanchez-Cespedes, M., Yang, S. C., Haasler, G. B., Kajdacsy-Balla, A., Demeure, M. 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A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1641 publisherName Nature Publishing Group title Germline mutations in HRAS proto-oncogene cause Costello syndrome. mimNumber 190070 referenceNumber 4 publisherAbbreviation NPG pubmedID 16170316 source Nature Genet. 37: 1038-1040, 2005. authors Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature08460 publisherName Nature Publishing Group title Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. mimNumber 190070 referenceNumber 5 publisherAbbreviation NPG pubmedID 19847166 source Nature 462: 108-112, 2009. authors Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., Frohling, S., Chan, E. 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Cell 21: 481-493, 2006. authors Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L., Saba, S. G., Yim, D., Fein, A., Perez de Castro, I., Li, C., Thompson, C. B., Cox, A. D., Philips, M. R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8955068 publisherName HighWire Press title Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. mimNumber 190070 referenceNumber 10 publisherAbbreviation HighWire pubmedID 8955068 source J. Biol. Chem. 271: 32491-32494, 1996. authors Bollag, G., Adler, F., elMasry, N., McCabe, P. 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Genet. 47: 859-862, 2010. authors Bourdeaut, F., Herault, A., Gentien, D., Pierron, G., Ballet, S., Reynaud, S., Paris, R., Schleiermacher, G., Baumann, C., Philippe-Chomette, P., Gauthier-Villars, M., Peuchmaur, M., Radvanyi, F., Delattre, O. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2648401 publisherName HighWire Press title Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. mimNumber 190070 referenceNumber 12 publisherAbbreviation HighWire pubmedID 2648401 source Proc. Nat. Acad. Sci. 86: 2403-2407, 1989. authors Burmer, G. C., Loeb, L. 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V. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60016-0 publisherName Elsevier Science title Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. mimNumber 190070 referenceNumber 15 publisherAbbreviation ES pubmedID 16773572 source Am. J. Hum. Genet. 79: 129-135, 2006. authors Carta, C., Pantaleoni, F., Bocchinfuso, G., Stella, L., Vasta, I., Sarkozy, A., Digilio, C., Palleschi, A., Pizzuti, A., Grammatico, P., Zampino, G., Dallapiccola, B., Gelb, B. D., Tartaglia, M. pubmedImages false publisherUrl http://www.elsevier.com/ source Nature Cell Biol. 14: 148-158, 2012. Note: Erratum: Nature Cell Biol. 14: 329 only, 2012. mimNumber 190070 authors Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., Wittinghofer, A., Bastiaens, P. I. H. title The GDI-like solubilizing factor PDE-delta sustains the spatial organization and signalling of Ras family proteins. referenceNumber 16 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6289320 publisherName HighWire Press title Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. mimNumber 190070 referenceNumber 17 publisherAbbreviation HighWire pubmedID 6289320 source Proc. Nat. Acad. Sci. 79: 4848-4852, 1982. authors Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M., Lowy, D. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23059812 publisherName HighWire Press title Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes. mimNumber 190070 referenceNumber 18 publisherAbbreviation HighWire pubmedID 23059812 source Hum. Molec. Genet. 22: 262-270, 2013. authors Cirstea, I. C., Gremer, L., Dvorsky, R., Zhang, S.-C., Piekorz, R. P., Zenker, M., Ahmadian, M. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/436642a publisherName Nature Publishing Group title Senescence in premalignant tumours. (Letter) mimNumber 190070 referenceNumber 19 publisherAbbreviation NPG pubmedID 16079833 source Nature 436: 642 only, 2005. authors Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguria, A., Zaballos, A., Flores, J. M., Barbacid, M., Beach, D., Serrano, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature711 publisherName Nature Publishing Group title Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. mimNumber 190070 referenceNumber 20 publisherAbbreviation NPG pubmedID 11793011 source Nature 415: 526-530, 2002. authors Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., Silva, A. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=1277176 publisherName HighWire Press title Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. mimNumber 190070 referenceNumber 21 publisherAbbreviation HighWire pubmedID 1277176 source Cancer Res. 36: 2690-2698, 1976. authors Cubilla, A. L., Fitzgerald, P. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(83)90510-X publisherName Elsevier Science title Altered gene products are associated with activation of cellular ras-k genes in human lung and colon carcinomas. mimNumber 190070 referenceNumber 22 publisherAbbreviation ES pubmedID 6825168 source Cell 32: 201-208, 1983. authors Der, C. J., Cooper, G. 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S., Pellicer, A., Lafarga, M., Crespo, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17332249 publisherName HighWire Press title Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. mimNumber 190070 referenceNumber 51 publisherAbbreviation HighWire pubmedID 17332249 source Blood 109: 5477-5480, 2007. authors Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., {and 10 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=6672765 publisherName HighWire Press title Regional chromosomal localization of N-ras, K-ras-1, K-ras-2 and myb oncogenes in human cells. mimNumber 190070 referenceNumber 52 publisherAbbreviation HighWire pubmedID 6672765 source Nucleic Acids Res. 11: 8221-8236, 1983. authors McBride, O. 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D. pubmedImages false articleUrl http://dx.doi.org/10.1038/nature08462 publisherName Nature Publishing Group title Requirement for NF-kappa-B signalling in a mouse model of lung adenocarcinoma. mimNumber 190070 referenceNumber 55 publisherAbbreviation NPG pubmedID 19847165 source Nature 462: 104-107, 2009. authors Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., Jacks, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature11156 publisherName Nature Publishing Group title Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. mimNumber 190070 referenceNumber 56 publisherAbbreviation NPG pubmedID 22722830 source Nature 486: 532-536, 2012. authors Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., Valtorta, E., Schiavo, R., Buscarino, M., Siravegna, G., Bencardino, K., Cercek, A., {and 14 others} pubmedImages false publisherUrl http://www.nature.com title Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma. mimNumber 190070 referenceNumber 57 pubmedID 8439212 source Ann. 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B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1749 publisherName Nature Publishing Group title Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. mimNumber 190070 referenceNumber 61 publisherAbbreviation NPG pubmedID 16474404 source Nature Genet. 38: 294-296, 2006. authors Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., {and 12 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=12727991 publisherName HighWire Press title RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. mimNumber 190070 referenceNumber 62 publisherAbbreviation HighWire pubmedID 12727991 source J. Clin. Endocr. Metab. 88: 2318-2326, 2003. authors Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., II, Tallini, G., Kroll, T. G., Nikiforov, Y. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Dispersion of the ras family of transforming genes to four different chromosomes in man. mimNumber 190070 referenceNumber 63 pubmedID 6843651 source Nature 302: 839-842, 1983. authors O'Brien, S. J., Nash, W. G., Goodwin, J. L., Lowry, D. R., Chang, E. H. pubmedImages false source Am. J. Hum. Genet. 37: A169 only, 1985. mimNumber 190070 authors O'Connell, P., Leppert, M., Hoff, M., Kumlin, E., Thomas, W., Cai, G., Law, M., White, R. title A linkage map for human chromosome 12. (Abstract) referenceNumber 64 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15294875 publisherName HighWire Press title Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. mimNumber 190070 referenceNumber 65 publisherAbbreviation HighWire pubmedID 15294875 source Hum. Molec. Genet. 13: 2303-2311, 2004. authors Oliveira, C., Westra, J. L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S., Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., {and 16 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=9203947 publisherName HighWire Press title High frequency of K-ras mutations in human colorectal hyperplastic polyps. mimNumber 190070 referenceNumber 66 publisherAbbreviation HighWire pubmedID 9203947 source Gut 40: 660-663, 1997. authors Otori, K., Oda, Y., Sugiyama, K., Hasebe, T., Mukai, K., Fujii, T., Tajiri, H., Yoshida, S., Fukushima, S., Esumi, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0901-3 publisherName Nature Publishing Group title A new verdict for an old convict. mimNumber 190070 referenceNumber 67 publisherAbbreviation NPG pubmedID 11528376 source Nature Genet. 29: 3-4, 2001. authors Pfeifer, G. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature09144 publisherName Nature Publishing Group title A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. mimNumber 190070 referenceNumber 68 publisherAbbreviation NPG pubmedID 20577206 source Nature 465: 1033-1038, 2010. authors Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., Pandolfi, P. P. pubmedImages false publisherUrl http://www.nature.com title Chromosomal localization of three human ras genes by in situ molecular hybridization. mimNumber 190070 referenceNumber 69 pubmedID 3856955 source Somat. Cell Molec. Genet. 11: 149-155, 1985. authors Popescu, N. C., Amsbaugh, S. C., DiPaolo, J. A., Tronick, S. R., Aaronson, S. A., Swan, D. C. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140673699042324 publisherName Elsevier Science title Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. mimNumber 190070 referenceNumber 70 publisherAbbreviation ES pubmedID 10609819 source Lancet 354: 2125-2129, 1999. authors Porta, M., Malats, N., Jariod, M., Grimalt, J. O., Rifa, J., Carrato, A., Guarner, L., Salas, A., Santiago-Silva, M., Corominas, J. M., Andreu, M., Real, F. X. pubmedImages false publisherUrl http://www.elsevier.com/ title Oncogene in solid human tumors. mimNumber 190070 referenceNumber 71 pubmedID 7144906 source Nature 300: 539-542, 1982. authors Pulciani, S., Santos, E., Lauver, A. V., Long, L. K., Aaronson, S. A., Barbacid, M. pubmedImages false articleUrl http://dx.doi.org/10.1038/418934a publisherName Nature Publishing Group title RAF/RAS oncogenes and mismatch-repair status. (Letter) mimNumber 190070 referenceNumber 72 publisherAbbreviation NPG pubmedID 12198537 source Nature 418: 934 only, 2002. authors Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.33635 publisherName John Wiley & Sons, Inc. title Walther, F. J.: Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation. mimNumber 190070 referenceNumber 73 publisherAbbreviation Wiley pubmedID 20949522 source Am. J. Med. Genet. 152A: 2816-2819, 2010. authors Rijntjes-Jacobs, E. G. J., Lopriore, E., Steggerda, S. J., Kant, S. G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198710083171504?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Mutational activation of the K-RAS oncogene: a possible pathogenetic factor in adenocarcinoma of the lung. mimNumber 190070 referenceNumber 74 publisherAbbreviation ATYPON pubmedID 3041218 source New Eng. J. Med. 317: 929-935, 1987. authors Rodenhuis, S., van de Wetering, M. L., Mooi, W. J., Evers, S. G., van Zandwijk, N., Bos, J. L. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=6328282 publisherName HighWire Press title Regional localization of two human cellular Kirsten ras genes on chromosomes 6 and 12. mimNumber 190070 referenceNumber 75 publisherAbbreviation HighWire pubmedID 6328282 source Molec. Cell. Biol. 4: 989-993, 1984. authors Sakaguchi, A. Y., Zabel, B. U., Grzeschik, K. H., Law, M. L., Ellis, R. W., Skolnick, E. M., Naylor, S. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6695174 publisherName HighWire Press title Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. mimNumber 190070 referenceNumber 76 publisherAbbreviation HighWire pubmedID 6695174 source Science 223: 661-664, 1984. authors Santos, E., Martin-Zanca, D., Reddy, E. P., Pierotti, M. A., Della Porta, G., Barbacid, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1748 publisherName Nature Publishing Group title Germline KRAS mutations cause Noonan syndrome. mimNumber 190070 referenceNumber 77 publisherAbbreviation NPG pubmedID 16474405 source Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006. authors Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2008&volume=73&issue=1&spage=62 publisherName Blackwell Publishing title Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome mimNumber 190070 referenceNumber 78 publisherAbbreviation Blackwell pubmedID 18042262 source Clin. Genet. 73: 62-70, 2008. authors Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., {and 15 others} pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16247081 publisherName HighWire Press title RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. mimNumber 190070 referenceNumber 79 publisherAbbreviation HighWire pubmedID 16247081 source Neurology 65: 1335-1336, 2005. authors Sharma, M. K., Zehnbauer, B. A., Watson, M. A., Gutmann, D. H. pubmedImages false publisherUrl http://highwire.stanford.edu title Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1. mimNumber 190070 referenceNumber 80 pubmedID 6308465 source Nature 304: 497-500, 1983. authors Shimizu, K., Birnbaum, D., Ruley, M. A., Fasano, O., Suard, Y., Edlund, L., Taparowsky, E., Goldfarb, M., Wigler, M. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1566048 publisherName HighWire Press title Identification of RAS oncogene mutations in the stool of patients with curable colorectal tumors. mimNumber 190070 referenceNumber 81 publisherAbbreviation HighWire pubmedID 1566048 source Science 256: 102-105, 1992. authors Sidransky, D., Tokino, T., Hamilton, S. R., Kinzler, K. W., Levin, B., Frost, P., Vogelstein, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3047672 publisherName HighWire Press title KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. mimNumber 190070 referenceNumber 82 publisherAbbreviation HighWire pubmedID 3047672 source Nucleic Acids Res. 16: 7773-7782, 1988. authors Smit, V. T. H. B. M., Boot, A. J. M., Smits, A. M. M., Fleuren, G. J., Cornelisse, C. J., Bos, J. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ijc.20567 publisherName John Wiley & Sons, Inc. title Mutations of BRAF and RAS are rare events in germ cell tumours. mimNumber 190070 referenceNumber 83 publisherAbbreviation Wiley pubmedID 15386408 source Int. J. Cancer 113: 329-335, 2005. authors Sommerer, F., Hengge, U. R., Markwarth, A., Vomschloss, S., Stolzenburg, J.-U., Wittekind, C., Tannapfel, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2012&volume=81&issue=6&spage=590 publisherName Blackwell Publishing title Two novel germline KRAS mutations: expanding the molecular and clinical phenotype. mimNumber 190070 referenceNumber 84 publisherAbbreviation Blackwell pubmedID 21797849 source Clin. Genet. 81: 590-594, 2012. authors Stark, Z., Gillessen-Kaesbach, G., Ryan, M. M., Cirstea, I. C., Gremer, L., Ahmadian, M. R., Savarirayan, R., Zenker, M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=21063026 publisherName HighWire Press title Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. mimNumber 190070 referenceNumber 85 publisherAbbreviation HighWire pubmedID 21063026 source Blood 117: 2887-2890, 2011. authors Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S. pubmedImages false publisherUrl http://highwire.stanford.edu title Detection of K-ras mutation in sputum by mutant-allele-specific amplification (MASA). mimNumber 190070 referenceNumber 86 pubmedID 8318987 source Hum. Mutat. 2: 112-117, 1993. authors Takeda, S., Ichii, S., Nakamura, Y. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng.211 publisherName Nature Publishing Group title Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. mimNumber 190070 referenceNumber 87 publisherAbbreviation NPG pubmedID 18758463 source Nature Genet. 40: 1240-1244, 2008. authors To, M. D., Wong, C. E., Karnezis, A. N., Del Rosario, R., Di Lauro, R., Balmain, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=12788883 publisherName HighWire Press title Specific pattern of RAS oncogene mutations in follicular thyroid tumors. mimNumber 190070 referenceNumber 88 publisherAbbreviation HighWire pubmedID 12788883 source J. Clin. Endocr. Metab. 88: 2745-2752, 2003. authors Vasko, V., Ferrand, M., Di Cristofaro, J., Carayon, P., Henry, J. F., De Micco, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=24264992 publisherName HighWire Press title Defining stem cell dynamics in models of intestinal tumor initiation. mimNumber 190070 referenceNumber 89 publisherAbbreviation HighWire pubmedID 24264992 source Science 342: 995-998, 2013. authors Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavare, S., Winton, D. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(82)90003-4 publisherName Elsevier Science title Fewer and fewer oncogenes. mimNumber 190070 referenceNumber 90 publisherAbbreviation ES pubmedID 6751559 source Cell 30: 3-4, 1982. authors Weinberg, R. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nature08702 publisherName Nature Publishing Group title Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. mimNumber 190070 referenceNumber 91 publisherAbbreviation NPG pubmedID 20072127 source Nature 463: 545-548, 2010. authors Wu, M., Pastor-Pareja, J. C., Xu, T. pubmedImages false publisherUrl http://www.nature.com title c-K-ras mutations in human carcinomas occur preferentially in codon 12. mimNumber 190070 referenceNumber 92 pubmedID 3330777 source Oncogene 1: 315-318, 1987. authors Yanez, L., Groffen, J., Valenzuela, D. M. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=16857939 publisherName HighWire Press title Receptor activation alters inner surface potential during phagocytosis. mimNumber 190070 referenceNumber 93 publisherAbbreviation HighWire pubmedID 16857939 source Science 313: 347-351, 2006. authors Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W. M., Philips, M., Levine, T., Kapus, A., Grinstein, S. pubmedImages false publisherUrl http://highwire.stanford.edu title Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. mimNumber 190070 referenceNumber 94 pubmedID 19661383 source Science 325: 1555-1559, 2009. authors Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., Diaz, L. A., Jr., Velculescu, V. E., Lengauer, C., Kinzler, K. W., Vogelstein, B., Papadopoulos, N. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=17056636 publisherName HighWire Press title Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. mimNumber 190070 referenceNumber 95 publisherAbbreviation HighWire pubmedID 17056636 source J. Med. Genet. 44: 131-135, 2007. authors Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14561760 publisherName HighWire Press title Photoreceptor cGMP phosphodiesterase delta subunit (PDE-delta) functions as a prenyl-binding protein. mimNumber 190070 referenceNumber 96 publisherAbbreviation HighWire pubmedID 14561760 source J. Biol. Chem. 279: 407-413, 2004. authors Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng721 publisherName Nature Publishing Group title Wildtype Kras2 can inhibit lung carcinogenesis in mice. mimNumber 190070 referenceNumber 97 publisherAbbreviation NPG pubmedID 11528387 source Nature Genet. 29: 25-33, 2001. authors Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L., Devereux, T. R., Jacks, T., Guan, K.-L., You, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature12205 publisherName Nature Publishing Group title Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling. mimNumber 190070 referenceNumber 98 publisherAbbreviation NPG pubmedID 23698361 source Nature 497: 638-642, 2013. authors Zimmerman, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H. pubmedImages false publisherUrl http://www.nature.com seeAlso Capon et al. (1983); Der and Cooper (1983); Sakaguchi et al. (1984); Shimizu et al. (1983)

entryList

entry status live allelicVariantExists true epochCreated 1015833600 geneMap geneSymbols ARX, ISSX, PRTS, MRXS1, MRX36, MRX54, MRX43, MRX87, MRX29, MRX32 sequenceID 14472 phenotypeMapList phenotypeMap phenotypeMimNumber 308350 mimNumber 300382 phenotypeInheritance X-linked recessive phenotypicSeriesMimNumber 308350 phenotypeMappingKey 3 phenotype Epileptic encephalopathy, early infantile, 1 phenotypeMimNumber 300215 mimNumber 300382 phenotypeInheritance X-linked phenotypicSeriesMimNumber 607432 phenotypeMappingKey 3 phenotype Hydranencephaly with abnormal genitalia phenotypeMimNumber 300215 mimNumber 300382 phenotypeInheritance X-linked phenotypicSeriesMimNumber 607432 phenotypeMappingKey 3 phenotype Lissencephaly, X-linked 2 phenotypeMimNumber 300419 mimNumber 300382 phenotypeInheritance None phenotypicSeriesMimNumber 309530 phenotypeMappingKey 3 phenotype Mental retardation, X-linked 29 and others phenotypeMimNumber 309510 mimNumber 300382 phenotypeInheritance X-linked recessive phenotypicSeriesMimNumber 309510 phenotypeMappingKey 3 phenotype Partington syndrome phenotypeMappingKey 3 mimNumber 300382 phenotypeInheritance X-linked phenotype Proud syndrome phenotypeMimNumber 300004 chromosomeLocationStart 25021810 chromosomeSort 126 chromosomeSymbol X mimNumber 300382 geneInheritance None confidence C mappingMethod REc, Fd geneName Aristaless-related homeobox, X-linked mouseMgiID MGI:1097716 mouseGeneSymbol Arx computedCytoLocation Xp21.3 cytoLocation Xp22.13 transcript uc004dbp.4 chromosomeLocationEnd 25034064 chromosome 23 contributors Cassandra L. Kniffin - updated : 10/30/2013 Cassandra L. Kniffin - updated : 2/5/2013 Cassandra L. Kniffin - updated : 9/20/2012 Cassandra L. Kniffin - updated : 1/5/2012 Cassandra L. Kniffin - updated : 12/20/2011 Cassandra L. Kniffin - updated : 10/31/2011 Cassandra L. Kniffin - updated : 7/12/2011 Cassandra L. Kniffin - updated : 11/29/2010 Patricia A. Hartz - updated : 9/9/2010 George E. Tiller - updated : 7/8/2010 Cassandra L. Kniffin - updated : 4/1/2010 Cassandra L. Kniffin - updated : 2/5/2009 Cassandra L. Kniffin - updated : 11/17/2008 Cassandra L. Kniffin - updated : 5/21/2008 Cassandra L. Kniffin - updated : 12/26/2007 Patricia A. Hartz - updated : 8/23/2007 Victor A. McKusick - updated : 8/16/2007 Marla J. F. O'Neill - updated : 1/9/2006 Marla J. F. O'Neill - updated : 12/28/2005 Marla J. F. O'Neill - updated : 8/4/2005 Marla J. F. O'Neill - updated : 10/8/2004 Victor A. McKusick - updated : 6/23/2004 Victor A. McKusick - updated : 2/26/2004 Victor A. McKusick - updated : 1/15/2004 Cassandra L. Kniffin - updated : 8/8/2003 Deborah L. Stone - updated : 6/16/2003 Cassandra L. Kniffin - updated : 4/1/2003 Cassandra L. Kniffin - updated : 3/27/2003 Victor A. McKusick - updated : 2/13/2003 clinicalSynopsisExists false mimNumber 300382 allelicVariantList allelicVariant status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs387906492 text In 2 unrelated families with EIEE1 ({308350}), 1 Canadian and 1 Belgian, {40:Stromme et al. (2002)} found that 8 and 2 male members, respectively, had an additional stretch of 7 tandem GCG repeats within the normal stretch of 10 GCG triplet repeats in exon 2. These families had been described by {3:Bruyere et al. (1999)} and {5:Claes et al. (1997)}. The effect of the mutation on the protein product was polyalanine expansion. The haplotype background of the mutation was different in the 2 families, indicating that a recurrent mutation had occurred. The normal tract of 16 alanine residues (amino acids 100-115) was expanded to 23. {36:Shoubridge et al. (2007)} showed that this polyalanine expansion mutation was associated with an increased propensity of ARX protein aggregation and a shift from nuclear to cytoplasmic localization. {19:Guerrini et al. (2007)} identified the (GCG)10+7 expansion in 6 boys, including 2 pairs of brothers, with a severe form of EIEE1, which they termed infantile epileptic-dyskinetic encephalopathy, including chorea and dystonia. All 6 boys also had severe mental retardation. Seizure onset occurred earlier in life than dystonia, which was severe and progressed to quadriplegic dyskinesia. Three children had recurrent, life-threatening status dystonicus. Brain MRI showed basal ganglia abnormalities in 4 patients. mutations ARX, (GCG)10+7 number 1 clinvarAccessions RCV000011936;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs387906493 text In a Norwegian family described by {41:Stromme et al. (1999)}, {40:Stromme et al. (2002)} found that 7 males with EIEE1 and West syndrome ({308350}) had a 24-bp duplication in exon 2 duplicating nucleotides 428-451. This resulted in a polyalanine expansion from a tract of 12 alanines (amino acids 144-155) to a tract of 20 alanines. Thus a different polyalanine tract in exon 2 was involved in these 2 instances. {40:Stromme et al. (2002)} found the same 24-bp duplication in the ARX gene in 2 families with X-linked mental retardation and in 2 families with Partington syndrome (PRTS; {309510}). The 2 families in which Partington syndrome was caused by the 24-bp duplication in exon 2 were an Australian family described by {29:Partington et al. (1988)} and a Belgian family described by {9:Frints et al. (2002)}. {44:Turner et al. (2002)} reviewed the 2 families reported by {40:Stromme et al. (2002)} with X-linked mental retardation and the 24-bp duplication. They concluded that the variable expression of the mutation in individuals from both families included manifestations of both West and Partington syndromes. In addition, 1 individual had autism and 2 had autistic behavior, 1 of whom also had epilepsy. In the MRX36 (see {309510}) family reported by {6:Claes et al. (1996)} with nonspecific X-linked mental retardation, {1:Bienvenu et al. (2002)} identified the 24-bp duplication in exon 2 of the ARX gene. {11:Frints et al. (2002)} suggested that the patients reported by {6:Claes et al. (1996)} had mild clinical features of PRTS. In the MRX43 family reported by {20:Hamel et al. (1999)} with X-linked mental retardation ({300419}), {1:Bienvenu et al. (2002)} identified the 24-bp duplication in exon 2 of the ARX gene. In the MRX76 family reported by {25:Kleefstra et al. (2002)}, {1:Bienvenu et al. (2002)} also identified the same 24-bp duplication. {39:Stromme et al. (2003)} described bilateral cyst-like cavities in both the cerebral and the cerebellar hemispheres. The patient was a 72-year-old man who lived in a home for the mentally handicapped. He was a member of a family in which X-linked mental retardation was due to a 24-bp duplication in exon 2 the ARX gene. Polyalanine expansions in 1 of the 2 polyalanine tracts in exon 2 of the ARX gene represent the most frequently occurring mutation in the ARX gene, and interfamilial as well as intrafamilial variability are observed. {46:Van Esch et al. (2004)} reported a family in which 4 males with mental retardation had the ARX 24-bp duplication. The proband also had agenesis of the corpus callosum, transsphenoidal encephalocele, and a hypothalamic variant of partial anterior hypopituitarism. The patient had been reported by {18:Grubben et al. (1990)} as being born with a median cleft lip and palate and a transsphenoidal encephalocele. One of his affected uncles had dysarthria and dystonic movements of the hands, consistent with Partington syndrome. None of the patients had seizures. {46:Van Esch et al. (2004)} noted that congenital basal encephaloceles are very rare and are classified into 4 types, of which the transsphenoidal type is the least frequent ({42:Suwanwela and Suwanwela, 1972}). The reported endocrine defects associated with basal encephalocele involve mostly anterior pituitary hormones. The pattern of ARX expression in the brain during embryonic development suggested a causal role for the mutated protein in the origin of the encephalocele in the proband. {30:Partington et al. (2004)} reported 3 families with X-linked mental retardation due to the 24-bp duplication in the ARX gene. They reviewed the clinical findings in the 46 MRX patients from 9 families that had been reported with this mutation and noted that mental retardation ranged from mild to severe. Infantile spasms (West syndrome; {308350}) occurred in 12.5% and less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. {30:Partington et al. (2004)} suggested that focal dystonia in association with mental retardation may be diagnostic of this mutation. {32:Poirier et al. (2005)} reported 2 brothers with mental retardation who had the 24-bp duplication in the ARX gene and whose healthy sister was heterozygous for the duplication. Their unaffected mother did not apparently carry the mutation, as determined by denaturing high-performance liquid chromatography (DHPLC) and by fragment size analysis, but semiquantitative fluorescent PCR revealed her to be a somatic mosaic, with 4% of her lymphocytes and 24% of her fibroblasts harboring the duplication. Because all 3 of her children received the affected X chromosome, {32:Poirier et al. (2005)} suggested that the level of mosaicism might be higher in the mother's germ cells. {38:Stepp et al. (2005)} identified the 24-bp duplication in affected individuals from 4 of 11 unrelated families designated as MRX29, MRX32, MRX33, and MRX38 with X-linked mental retardation ({300419}). The findings suggested that the 24-bp duplication is the most common mutation in nonsyndromic XLMR families linked to Xp22.1. {26:Laperuta et al. (2007)} identified the 24-bp duplication of the ARX gene in 5 affected men from an Italian family designated MRX87 with X-linked mental retardation ({300419}). There was marked intrafamilial variation with cognitive deficits ranging from moderate to severe. There were no dysmorphic features, but 3 patients had flat feet, 2 had urinary incontinence, and 1 had a congenital hindbrain herniation of the cerebellar tonsils. The oldest patient, age 67 years, had other neurologic signs, including pyramidal hypotonia, extensor plantar responses, hypoacusis, and signs of dementia. Carrier women were unaffected. mutations ARX, 24-BP DUP, NT428 number 2 alternativeNames PARTINGTON SYNDROME, INCLUDED;; MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT SEIZURES, ARX-RELATED, INCLUDED clinvarAccessions RCV000011938;;1;;;RCV000033212;;1;;;RCV000011937;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs104894743 text {35:Scheffer et al. (2002)} described 6 males in an Australian family with a severe form of EIEE1 ({308350}), which they termed X-linked myoclonic epilepsy with mental retardation, and spasticity. {35:Scheffer et al. (2002)} and {40:Stromme et al. (2002)} identified, in affected members of this family, a 1058C-T transition in the ARX gene, resulting in a pro353-to-leu (P353L) substitution. mutations ARX, PRO353LEU number 3 clinvarAccessions RCV000011939;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 text In a Norwegian family, {40:Stromme et al. (2002)} found that 2 males with EIEE1 ({308350}) had deletion of 1,517 bp in the ARX gene that removed 816 bp of intron 4 and 701 bp of exon 5. The deletion was predicted to result in an alternative carboxy-terminal of the ARX protein (R483fs). mutations ARX, 1,517-BP DEL number 4 clinvarAccessions RCV000011940;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In a proband with X-linked lissencephaly with abnormal genitalia (LISX2; {300215}), {24:Kitamura et al. (2002)} found deletion of nucleotides 420-451 in exon 2 of the ARX gene, resulting in a truncated protein consisting of 140 N-terminal amino acids with 85 amino acid residues artificially added by the frameshift mutation. mutations ARX, 32-BP DEL, NT420 number 5 clinvarAccessions RCV000011941;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In their proband 2 with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found deletion of nucleotide 790 (790delC) in exon 2 of the ARX gene, resulting in a truncated protein consisting of 263 N-terminal amino acids with 60 amino acid residues artificially added. In a patient with XLAG, {45:Uyanik et al. (2003)} identified the 790C deletion. The patient's mother was a heterozygous carrier for the mutation. The predicted mutated protein lacks the homeobox domain. mutations ARX, 1-BP DEL, 790C number 6 clinvarAccessions RCV000011942;;1 status live name LISSENCEPHALY, X-LINKED, 2 dbSnps rs111033612 text In their proband 3 with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found a 995G-A transition in exon 2 of the ARX gene, resulting in the amino acid substitution arg332 to his (R332H). The mother was heterozygous for the mutation. In in vitro studies, {4:Cho et al. (2012)} found that the mutant R332H protein had no DNA binding activity and showed significantly decreased transcriptional repression activity compared to wildtype ARX. mutations ARX, ARG332HIS number 7 clinvarAccessions RCV000145064;;1;;;RCV000011943;;1 status live name LISSENCEPHALY, X-LINKED, 2 dbSnps rs104894740 text In their proband 4 with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found a 1117C-T transition in exon 3 of the ARX gene, resulting in premature termination (gln373 to ter; Q373X). The mother was heterozygous for the mutation. mutations ARX, GLN373TER number 8 clinvarAccessions RCV000011944;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In their proband 5 with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found a single-nucleotide insertion at nucleotide 1188 (1188insC) in exon 4 of the ARX gene, resulting in a truncated protein containing the 396 N-terminal amino acids plus an additional 134 residues. mutations ARX, 1-BP INS, 1188C number 9 clinvarAccessions RCV000011945;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In their proband 6 with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found apparent deletion of exons 1 and 2 of the ARX gene. mutations ARX, EX1-2DEL number 10 clinvarAccessions RCV000011946;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In their proband 7 with X-linked lissencephaly with abnormal genitalia, {24:Kitamura et al. (2002)} found a single-nucleotide deletion at nucleotide 1372 (1372delG) in exon 4 of the ARX gene, resulting in a truncated protein consisting of the 457 N-terminal amino acids accompanied by 4 abnormal amino acids. mutations ARX, 1-BP DEL, 1372G number 11 clinvarAccessions RCV000011947;;1 status live name LISSENCEPHALY, X-LINKED, 2 dbSnps rs104894741 text In their probands 8 and 9 (who were brothers) with X-linked lissencephaly with abnormal genitalia ({300215}), {24:Kitamura et al. (2002)} found a 1028T-A transversion in exon 2 of the ARX gene, resulting in the amino acid substitution leu343 to gln (L343Q). Their mother was heterozygous for the mutation, and their father and maternal grandparents were normal. In in vitro studies, {4:Cho et al. (2012)} found that the L343Q mutant ARX had no DNA binding ability, although it retained transcriptional repression activity similar to that of the wildtype protein when tested in a reporter gene assay system that did not require the DNA-binding domain of ARX. Thus, the mutant protein has no functional repression of ARX targets, possibly explaining the severe phenotype. mutations ARX, LEU343GLN number 12 clinvarAccessions RCV000011948;;1 status live name MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT SEIZURES, ARX-RELATED dbSnps rs104894744,rs28936077 text In a 3-generation family with nonspecific X-linked mental retardation ({300419}) and designated MRX54, {1:Bienvenu et al. (2002)} identified a 98T-C transition in the ARX gene, which was predicted to result in a leu33-to-pro (L33P) substitution in the octapeptide domain. mutations ARX, LEU33PRO number 13 clinvarAccessions RCV000011949;;1 status live name MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT SEIZURES, ARX-RELATED dbSnps rs28935479 text In a family with nonspecific X-linked mental retardation ({300419}), {1:Bienvenu et al. (2002)} identified an 856G-A transition in the ARX gene, which was predicted to result in a gly286-to-ser (G286S) substitution. mutations ARX, GLY286SER number 14 clinvarAccessions RCV000011950;;1 status live name CORPUS CALLOSUM, AGENESIS OF, WITH ABNORMAL GENITALIA dbSnps rs104894745 text In affected members of the family reported by {33:Proud et al. (1992)} in which 3 males had X-linked mental retardation, agenesis of the corpus callosum, and abnormal genitalia ({300004}), {21:Kato et al. (2004)} identified a 998C-A transversion in exon 2 of the ARX gene, resulting in a thr333-to-asn (T333N) mutation. Two female mutation carriers were less severely impaired, but had spastic quadriplegia and seizures. One obligate carrier was retarded with emotional problems, whereas another obligate carrier and her daughter were clinically normal. The authors noted that these findings were consistent with X-linked inheritance with variable expression in females. In in vitro studies, {4:Cho et al. (2012)} found that the mutant T333N protein bound DNA with lower affinity than wildtype ARX, but also had significantly decreased transcriptional repression activity compared to wildtype ARX. mutations ARX, THR333ASN number 15 clinvarAccessions RCV000011951;;1;;;RCV000145066;;1 status live name HYDRANENCEPHALY WITH ABNORMAL GENITALIA dbSnps rs104894746 text In a sporadic case of hydranencephaly with abnormal genitalia (see {300215}), {21:Kato et al. (2004)} identified an 1105G-T transversion in exon 3 of the ARX gene, resulting in a glu369-to-ter (E369X) change. mutations ARX, GLU369TER number 16 clinvarAccessions RCV000011952;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 text In 2 of 3 unrelated male patients with EIEE1 that progressed to West syndrome ({308350}), {22:Kato et al. (2007)} found a hemizygous, de novo, 33-bp duplication in exon 2 of the ARX gene. This mutation was thought to expand the original 16 alanine residues to 27 alanine residues in the first polyalanine tract of the ARX protein. {22:Kato et al. (2007)} pointed to a total of 9 genes with expansion of the polyalanine tract resulting in human diseases. Clinical observations demonstrated the correlation between the length of the repeat and the severity of the clinical phenotype. mutations ARX, 33-BP DUP number 17 clinvarAccessions RCV000011953;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE text This variant, formerly titled MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT SEIZURES, ARX-RELATED, has been reclassified based on the findings of {7:Conti et al. (2011)}. In a boy with nonsyndromic X-linked mental retardation ({300419}), {43:Troester et al. (2007)} identified a 24-bp in-frame deletion within exon 2 of the ARX gene, removing nucleotides 441 to 464, and resulting in the removal of 8 alanines from the second polyalanine repeat in exon 2. The patient's unaffected mother and sister were heterozygous for the deletion. A common pathogenic 24-bp duplication in the ARX gene ({300382.0002}) also occurs in exon 2. {7:Conti et al. (2011)} reported 2 unrelated girls with mental retardation and seizures who inherited a 24-bp deletion (441_464del) in exon 2 of the ARX gene, resulting in a contraction of 8 alanines in the second polyA tract of ARX. Each girl inherited the deletion from an unaffected parent, a father in 1 case and a mother in the other. Two healthy female relatives of 1 of the patients also carried the deletion. The deletion was not found in 150 controls, nor in 65 additional patients with mental retardation and epilepsy. {7:Conti et al. (2011)} concluded that this contraction in ARX is not pathogenic, but rather represents a rare, benign polymorphism. mutations ARX, 24-BP DEL, NT441 number 18 clinvarAccessions RCV000011954;;1 status live name LISSENCEPHALY, X-LINKED, 2 text In an Irish boy with X-linked lissencephaly with ambiguous genitalia ({300215}), {21:Kato et al. (2004)} identified a hemizygous 1-bp deletion (617delG) in exon 2 of the ARX gene, resulting in a frameshift and premature termination. At birth, he had very small penis, small hypoplastic scrotum, and undescended testes. He developed continuous seizure activity soon after birth, and eye examination suggested optic nerve hypoplasia. Brain imaging showed complete agenesis of the corpus callosum and lissencephaly in a posterior to anterior gradient. He had profoundly delayed development and died at age 18 months. Family history revealed an older stillborn brother with hydranencephaly and a sister with seizures, mental retardation, and partial agenesis of the corpus callosum, who carried the mutation. A maternal aunt was a genotypic male with ambiguous genitalia, neonatal seizures, and early death. The proband's unaffected mother was an obligate carrier. mutations ARX, 1-BP DEL, 617G number 19 clinvarAccessions RCV000011955;;1 status live name LISSENCEPHALY, X-LINKED, 2 dbSnps rs267606666 text In affected members of 2 unrelated families with X-linked lissencephaly with ambiguous genitalia ({300215}) reported by {2:Bonneau et al. (2002)}, {21:Kato et al. (2004}) identified a hemizygous 232G-T transversion in exon 2 of the ARX gene, resulting in a glu78-to-ter (E78X) substitution. A total of 4 carrier females in the families were mildly affected, with agenesis of the corpus callosum in all, learning disabilities in 1, and mental retardation in 1. mutations ARX, GLU78TER number 20 clinvarAccessions RCV000011956;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 text In a female with EIEE1 ({308350}), {47:Wallerstein et al. (2008)} identified a heterozygous 1-bp deletion (1465delG) in exon 5 of the ARX gene, resulting in a frameshift and premature termination of the protein at codon 491. She was the product of a twin pregnancy conceived by in vitro fertilization with a donor egg and the father's sperm. She developed severe intractable myoclonic seizures at age 4 months, consistent with epileptic encephalopathy. She had delayed development, with poor visual tracking and poor speech development. Mild dysmorphic features, including epicanthal folds, and mildly low-set ears were also noted. The other twin was apparently unaffected. The findings indicated that haploinsufficiency of the ARX gene can result in a severe phenotype in females. mutations ARX, 1-BP DEL, 1465G number 21 clinvarAccessions RCV000011957;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs587776869 text In a boy with EIEE1 ({308350}), {34:Reish et al. (2009)} identified a heterozygous in-frame 27-bp duplication (430_456dup) in exon 2 of the ARX gene, resulting in the expansion of polyalanine tract-2 by 9 alanines, from wildtype 12A to 21A. The duplication partially overlapped with the common 24-bp duplication ({300382.0002}). The 27-bp duplication was identified in the patient's unaffected Ashkenazi mother and maternal grandmother, but not in the unaffected father who was of Ashkenazi, Egyptian, and Iraqi descent. Tissue levels in the maternal grandmother were lower than in the mother (blood, 18.3% and 40.4%, respectively; buccal cells, 2.4% and 35.9%, respectively). These findings suggested postmitotic somatic mosaicism in the grandmother, consistent with a de novo event occurring at an early embryonic stage in a multipotent cell, which gave rise predominantly to the mesoderm (blood) compared to the ectoderm (buccal fibroblasts). Haplotype analysis suggested that the mutation came from the maternal great-grand paternal allele; this individual was unaffected. The patient had onset of refractory infantile spasms at age 2 months, followed by hypsarrhythmia and significant developmental delay. Family history revealed that 2 maternal uncles had a similar phenotype, with death in infancy. {34:Reish et al. (2009)} proposed that the severe phenotype was due to the larger duplication in polyalanine tract-2 of ARX. mutations ARX, 27-BP DUP, NT430 number 22 clinvarAccessions RCV000022855;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs398122854 text In 2 male first cousins with EIEE1 ({308350}), {12:Fullston et al. (2010)} identified an 81C-G transversion in exon 1 of the ARX gene, resulting in a tyr27-to-ter (Y27X) substitution. The severely truncated 26-residue protein lacked all of the functional domains and was predicted to be a null mutation. Overexpression of the mutation in HEK293 cells showed the presence of an N-terminally truncated ARX protein that likely used a start codon at residue 41 (M41_C562), with no detection of the Y27X protein. Although the patients had a severe form of the disorder with early-onset refractory seizures and essentially no developmental progress, neither had evidence of pachygyria or lissencephaly on brain imaging and neither had ambiguous genitalia. As null ARX mutations are usually associated with lissencephaly and ambiguous genitalia (XLAG; {300215}), {12:Fullston et al. (2010)} speculated that some partially functioning ARX protein was formed by reinitiation of mRNA translation in these patients. mutations ARX, TYR27TER number 23 clinvarAccessions RCV000022856;;1 status live name EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 dbSnps rs387906715 text In a family with EIEE1 ({308350}), {16:Giordano et al. (2010)} identified a 1604T-A transition in exon 5 of the ARX gene, resulting in a leu535-to-gln (L535Q) substitution in a highly conserved residue in the Aristaless domain. The mutation was not found in 150 control chromosomes. The 2 affected boys had onset of severe refractory seizures in early infancy. EEG showed a suppression burst pattern, which later evolved to hypsarrhythmia. One of the boys had poor overall growth, and both developed progressive microcephaly associated with intellectual impairment and spastic tetraparesis. Brain MRI at first was normal in both children, but showed diffuse brain atrophy around 2 years of age. {16:Giordano et al. (2010)} noted that the mutation in this family did not involve an expanded polyalanine tract, indicating that missense mutations in the ARX gene can also lead to a severe phenotype. mutations ARX, LEU535GLN number 24 clinvarAccessions RCV000022857;;1 prefix * titles preferredTitle ARISTALESS-RELATED HOMEOBOX, X-LINKED; ARX textSectionList textSection textSectionTitle Description textSectionContent The ARX gene encodes the Aristaless-related homeobox protein, which belongs to the Aristaless-related subset of the paired (Prd) class of homeodomain proteins. Homeodomain transcription factors play crucial roles in cerebral development and patterning ({1:Bienvenu et al., 2002}). {15:Gecz et al. (2006)} provided a review of the ARX gene and its role in human disease. textSectionName description textSectionTitle Cloning textSectionContent {40:Stromme et al. (2002)} identified the ARX gene in the genomic sequence of PAC clone 258N20 (GenBank {GENBANK AC002504}), in the vicinity of the gene encoding DNA polymerase-alpha (POLA; {312040}), which maps to Xp22.3-p21.1. The open reading frame spans 1,686 bp and encodes a protein of 562 amino acids. Northern blot and expressed sequence tag (EST) analyses indicated that ARX is expressed predominantly in fetal and adult brain and skeletal muscle. {40:Stromme et al. (2002)} detected a single 2.8-kb ARX mRNA isoform in brain and 2 additional, smaller ARX mRNAs in skeletal muscle. The mouse and zebrafish ARX orthologs are expressed predominantly in forebrain (cerebral cortex) and floor plate, which suggested that ARX protein is important for the maintenance of specific neuronal subtypes in the cerebral cortex and axonal guidance in the floor plate ({28:Miura et al., 1997}). textSectionName cloning textSectionTitle Gene Structure textSectionContent {40:Stromme et al. (2002)} determined that the ARX gene is composed of 5 coding exons and encompasses a genomic region of roughly 12.5 kb. textSectionName geneStructure textSectionTitle Mapping textSectionContent According to {40:Stromme et al. (2002)}, the ARX gene is located approximately 6.7 kb from the 3-prime end of the POLA gene, which maps to Xp22.3-p21.1. The ARX and POLA genes are in tail-to-tail orientation. textSectionName mapping textSectionTitle Gene Function textSectionContent Using yeast 2-hybrid and coimmunoprecipitation analyses, {36:Shoubridge et al. (2007)} found that ARX interacted via its homeodomain with IPO13 ({610411}), a mediator of nuclear import. By genomewide microarray analysis of subpallia microdissected from embryonic day-14.5 mouse embryos, {14:Fulp et al. (2008)} identified 84 genes that were dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and transcriptional regulation. Chromatin immunoprecipitation and reporter gene assays confirmed that Arx bound to and downregulated expression of the transcription factors Lmo1 ({186921}), Ebf3 ({607407}), and Shox2 ({602504}). {14:Fulp et al. (2008)} also identified a set of genes involved in interneuron development that were regulated by both Arx and Dlx1 ({600029})/Dlx2 ({126255}). They concluded that ARX plays multiple roles in forebrain development that can be both dependent and independent of DLX1/DLX2. {4:Cho et al. (2012)} determined that ARX homeodomain binds to the 5-prime-TAAT-3-prime sequence of DNA and requires a T or C adjacent to the 5-prime end, and a T adjacent to the 3-prime end. These binding preferences were altered by ARX deletion mutants involving the homeodomain region, suggesting that binding preferences can vary and depend on protein structure. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Mutations in the ARX gene underlie a phenotypic spectrum comprising a nearly continuous series of X-linked developmental disorders ranging from lissencephaly (LISX2; {300215}) to agenesis of the corpus callosum with abnormal genitalia ({300004}) to infantile spasms without brain malformations (EIEE1; {308350}) to syndromic ({309510}) and nonsyndromic ({300419}) mental retardation. Male ARX mutation carriers are severely affected, whereas female mutation carriers may be unaffected or have a milder phenotype ({21:Kato et al., 2004}; {47:Wallerstein et al., 2008}; {27:Marsh et al., 2009}). In a review of X-linked mental retardation, {10:Frints et al. (2002)} stated that the identification of 11 genes underlying X-linked mental retardation emphasized that both syndromic and nonspecific X-linked mental retardation may be caused by mutations in the same gene. In addition to ARX, they listed the RSK2 ({300075}) and MECP2 genes ({300005}). {37:Shoubridge et al. (2010)} provided a review of the phenotypic spectrum of disorders caused by mutation in the ARX gene, noting that intra- and interfamilial pleiotropy is a hallmark of such disorders. {31:Poeta et al. (2013)} found that ARX bound to conserved noncoding elements in the 5-prime region of the KDM5C gene ({314690}), resulting in increased expression of KDM5C. In vitro cellular expression studies showed that transfection of 5 ARX mutants (see, e.g., {300382.0022}) that cause intellectual disability or severe epilepsy resulted in variably decreased activation of the KDM5C gene compared to wildtype ARX. The changes in polyA repeats caused hypomorphic ARX alterations, which exhibit a decreased transactivity and reduced, but not abolished, binding to the KDM5C regulatory region. The altered functioning of the mutants tested correlated with the severity of the associated phenotype. Quantitative RT-PCR studies showed a dramatic decrease of Kdm5c mRNA in murine Arx-null embryonic and neural stem cells. The decrease in the KDM5C content during in vitro neuronal differentiation inversely correlated with increased histone regulation, as measured by H3K4me3 levels. The findings linked ARX polyA expansions to KDM5C, mutations of which cause a similar phenotype, and established that ARX polyA alterations damage the regulation of KDM5C expression, suggesting a pathogenic pathway involving changes in chromatin remodeling in these neurologic disorders. Early-Onset Epileptic Encephalopathy 1 and Partington Syndrome West syndrome consists of infantile spasms, an electroencephalographic pattern of hypsarrhythmia and subsequent mental retardation. Early-onset epileptic encephalopathy-1 is an X-linked subgroup of West syndrome (ISSX1, EIEE1; {308350}) identified by {8:Feinberg and Leahy (1977)} and mapped to the short arm of the X chromosome ({3:Bruyere et al., 1999}). {40:Stromme et al. (2002)} identified the ARX gene in the critical mapping region and considered it a candidate gene primarily on the basis of its expression pattern in fetal, infant, and adult brain. In 7 families with mental retardation and various forms of epilepsy consistent with X-linked West syndrome, {40:Stromme et al. (2002)} identified 2 different recurrent mutations that resulted in expansion of polyalanine (PolyA) tracts of the ARX protein: a GCG expansion ({300382.0001}) and a 24-bp duplication ({300382.0002}). These were predicted to cause protein aggregation, similar to other polyalanine and polyglutamine disorders. {40:Stromme et al. (2002)} also identified a missense mutation within the ARX homeodomain (P353L; {300382.0002}) and a truncation mutation ({300382.0004}). They concluded that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy. At least 6 other genes had been identified in which polyalanine expansions cause human disease: HOXD13 in synpolydactyly ({142989.0001}), RUNX2 in cleidocranial dysplasia ({600211.0003}), PABP2 in oculopharyngeal muscular dystrophy ({602279.0001}), ZIC2 in holoprosencephaly ({603073.0003}), HOXA13 in hand-foot-genital syndrome ({142959.0003}), and FOXL2 in type II blepharophimosis/ptosis/epicanthus inversus syndrome ({605597.0002}). All other polyA and polyQ expansion disorders are inherited almost exclusively in an autosomal dominant manner, whereas the 2 ARX expansion mutations segregate as X-linked recessive. Female carriers are not clinically affected and show a random pattern of X-inactivation in blood leukocytes, suggesting a loss rather than a gain of function. {40:Stromme et al. (2002)} found the 24-bp duplication in the ARX gene in 2 families with X-linked mental retardation and in 2 families with Partington syndrome (PRTS; {309510}). The 2 families in which Partington syndrome was caused by the 24-bp duplication in exon 2 were an Australian family described by {29:Partington et al. (1988)} and a Belgian family described by {9:Frints et al. (2002)}. {17:Gronskov et al. (2004)} screened 682 Danish males with nonspecific developmental delay/mental retardation for polyalanine expansions in ARX and identified 4 individuals with changes in fragment size. Two patients had a single polyalanine expansion (333GCG), which was also identified in 1 of 188 normal males, and 1 patient had a previously reported polymorphism involving a 24-bp deletion. Another patient had a triple alanine expansion, but its disease-causing potential could not be evaluated further due to the unavailability of family members for testing. {17:Gronskov et al. (2004)} concluded that the previously described polyalanine expansions in ARX are not a common cause of mental retardation. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX ({300382.0002}) causes mental retardation and seizures, including those of West syndrome, in males. {22:Kato et al. (2007)} screened for mutation in ARX in 3 unrelated male patients with EIEE that progressed to West syndrome and found a hemizygous, de novo, 33-bp duplication in the first polyalanine tract ({300382.0017}) in 2. This mutation was thought to expand the original 16 alanine residues to 27 alanine residues. The observation that EIEE has a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more severe phenotypes in EIEE than in West syndrome. {22:Kato et al. (2007)} referred to EIEE with a suppression-burst pattern as the Ohtahara syndrome. X-Linked Lissencephaly with Abnormal Genitalia {24:Kitamura et al. (2002)} used phenotypic analysis of the Arx knockout mouse to identify ARX as the gene associated with an X-linked human brain malformation, X-linked lissencephaly with abnormal genitalia (LISX2; {300215}). Because the results of phenotypic analysis of the Arx knockout mouse, as well as the chromosomal localization of the ARX gene, implicated it as a plausible XLAG candidate gene, {24:Kitamura et al. (2002)} looked for mutations in ARX in 8 XLAG probands and identified 8 different mutations ({300382.0005}-{300382.0012}). Agenesis of the Corpus Callosum with Abnormal Genitalia In affected members of the family reported by {33:Proud et al. (1992)} in which 3 males had X-linked mental retardation, agenesis of the corpus callosum, and abnormal genitalia ({300004}), {21:Kato et al. (2004)} identified a mutation in the ARX gene (T333N; {300382.0015}). Two female mutation carriers were less severely impaired, but had spastic quadriplegia and seizures. One obligate carrier was retarded with emotional problems, whereas another obligate carrier and her daughter were clinically normal. The authors noted that these findings were consistent with X-linked inheritance with variable expression in females. X-Linked Mental Retardation, ARX-Related In 9 familial cases of nonspecific X-linked mental retardation ({300419}), {1:Bienvenu et al. (2002)} reported missense mutations and in-frame duplications/insertions leading to expansions of polyalanine tracts in the ARX gene ({300382.0002}; {300382.0013}; {300382.0014}). In mouse embryos, Arx expression was specific to the telencephalon and ventral thalamus, with an absence of expression in the cerebellum throughout development. The authors suggested that since there was an absence of detectable brain malformations in these patients harboring ARX mutations, ARX may have an essential role in mature neurons, required for the development of cognitive abilities. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent In a review of 29 males with ARX mutations, {21:Kato et al. (2004)} found that those with premature termination or nonsense mutations had brain malformation syndromes, including LISX2 ({300215}) and Proud syndrome ({300004}), whereas those with expansion of the polyalanine tract ({300382.0001} and {300382.0002}) had epileptic encephalopathy ({308350}) or mental retardation ({309510}; {300419}) without brain malformations. Missense mutations were equally divided between the 2 groups, but the more severe phenotypes correlated with mutations in highly conserved regions. {12:Fullston et al. (2010)} identified a truncating mutation in the ARX gene (Y27X; {300382.0023}) in 2 male first cousins with EIEE1 ({308350}) who had no evidence of pachygyria or lissencephaly on brain imaging and no ambiguous genitalia. Overexpression of the mutation in HEK293 cells showed the presence of an N-terminally truncated ARX protein that likely used a start codon at residue 41 (M41_C562), with no detection of a Y27X protein. As null ARX mutations are usually associated with lissencephaly and ambiguous genitalia (XLAG; {300215}), {12:Fullston et al. (2010)} speculated that some partially functioning ARX protein was formed by reinitiation of mRNA translation in these patients. {13:Fullston et al. (2011)} identified 6 different mutations in the ARX gene in 8 (1.3%) of 613 probands with intellectual disability who were screened for mutations in this gene. Five duplication mutations of various sizes and 3 point mutations were identified. In vitro functional expression studies in HEK293 cells showed that mutant protein mislocalization and cytoplasmic aggregation increased as a function of polyA tract lengths and correlated with phenotypic severity. Similarly, extent of protein mislocalization of homeodomain mutations also correlated with clinical severity. The findings suggested an emerging genotype/cellular phenotype correlation, and {13:Fullston et al. (2011)} suggested that increased cellular mislocalization is related to mutant protein dysfunction. In in vitro studies, {4:Cho et al. (2012)} found that missense mutations in the homeodomain of ARX caused a reduction in transcriptional repressor activity. The R332H ({300382.0007}) and R332P mutant proteins had absence of DNA binding ability, as well as significantly decreased transcriptional repression activity compared to wildtype ARX when tested in a reporter gene assay system that did not require the DNA-binding domain of ARX. The L343Q mutant protein lacked DNA binding ability, but retained transcriptional repression activity in this artificial assay. These mutations are all associated with the brain malformation lissencephaly. In contrast, the T333N ({300382.0015}) mutant protein retained some DNA binding ability, but also showed decreased transcriptional repression activity; this mutation is associated with agenesis of the corpus callosum, a slightly less severe phenotype. The findings suggested that the phenotypic severity associated with ARX mutations results from alterations of both DNA binding ability and abrogation of transcriptional activity. textSectionName genotypePhenotypeCorrelations textSectionTitle Animal Model textSectionContent {24:Kitamura et al. (2002)} demonstrated that male embryonic mice with mutations in the Arx gene died within the first born natal day. Neonatal mutants developed small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of XLAG in humans. {27:Marsh et al. (2009)} found that male mice with conditional deletion of the Arx gene from ganglionic eminence-derived neurons, including cortical interneurons, developed a variety of seizure types and EEG abnormalities in early life, including those that resembled human infantile spasms. About half of the female mice with a single mutant conditional allele also developed seizures. Immunohistochemical studies showed a reduction in calbindin ({114050})- and calretinin ({114051})-labeled neurons in the neocortex as well as impaired development of interneurons in the hippocampus. {27:Marsh et al. (2009)} also found that 8 (32%) of 25 human female carriers of ARX mutations had seizures, neurocognitive deficits, and/or corpus callosum agenesis. The findings indicated that disruption of the interneuron subpopulation is important in the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. {23:Kitamura et al. (2009)} generated 3 types of mice with knocked-in Arx mutations equivalent to the human ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation (P353L, {300382.0003}; 333ins(GCG)7, {300382.0001}). Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and life span from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum, and ventral forebrain nuclei when compared with wildtype mice. {23:Kitamura et al. (2009)} concluded that a causal relationship exists between ARX mutations and the pleiotropic phenotype in mice, suggesting that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors. textSectionName animalModel geneMapExists true editHistory carol : 10/31/2013 ckniffin : 10/30/2013 carol : 9/9/2013 ckniffin : 2/6/2013 carol : 2/5/2013 ckniffin : 2/5/2013 carol : 9/21/2012 ckniffin : 9/20/2012 carol : 1/13/2012 carol : 1/11/2012 ckniffin : 1/5/2012 carol : 12/22/2011 ckniffin : 12/20/2011 carol : 11/22/2011 alopez : 11/2/2011 carol : 11/1/2011 ckniffin : 10/31/2011 wwang : 7/25/2011 ckniffin : 7/12/2011 wwang : 11/30/2010 ckniffin : 11/29/2010 mgross : 9/13/2010 mgross : 9/13/2010 terry : 9/9/2010 wwang : 7/22/2010 terry : 7/8/2010 carol : 4/2/2010 ckniffin : 4/1/2010 wwang : 2/17/2009 ckniffin : 2/5/2009 wwang : 12/3/2008 wwang : 12/3/2008 wwang : 11/25/2008 ckniffin : 11/17/2008 ckniffin : 7/10/2008 wwang : 5/23/2008 ckniffin : 5/21/2008 wwang : 1/4/2008 ckniffin : 12/26/2007 ckniffin : 11/19/2007 mgross : 8/30/2007 terry : 8/23/2007 alopez : 8/20/2007 terry : 8/16/2007 ckniffin : 1/12/2006 wwang : 1/9/2006 wwang : 1/5/2006 terry : 12/28/2005 wwang : 8/4/2005 terry : 8/4/2005 carol : 10/29/2004 terry : 10/8/2004 terry : 7/27/2004 tkritzer : 6/29/2004 ckniffin : 6/29/2004 terry : 6/23/2004 carol : 3/1/2004 tkritzer : 2/27/2004 terry : 2/26/2004 cwells : 1/20/2004 terry : 1/15/2004 ckniffin : 8/8/2003 carol : 6/16/2003 carol : 6/9/2003 carol : 4/4/2003 carol : 4/3/2003 ckniffin : 4/1/2003 ckniffin : 3/27/2003 tkritzer : 2/13/2003 cwells : 2/12/2003 alopez : 11/4/2002 carol : 10/16/2002 alopez : 10/16/2002 ckniffin : 10/2/2002 alopez : 4/12/2002 alopez : 3/11/2002 dateCreated Mon, 11 Mar 2002 03:00:00 EST creationDate Victor A. McKusick : 3/11/2002 epochUpdated 1383202800 dateUpdated Thu, 31 Oct 2013 03:00:00 EDT referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11971879 publisherName HighWire Press title ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. mimNumber 300382 referenceNumber 1 publisherAbbreviation HighWire pubmedID 11971879 source Hum. Molec. Genet. 11: 981-991, 2002. authors Bienvenu, T., Poirier, K., Friocourt, G., Bahi, N., Beaumont, D., Fauchereau, F., Ben Jeema, L., Zemni, R., Vinet, M.-C., Francis, F., Couvert, P., Gomot, M., {and 11 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.10119 publisherName John Wiley & Sons, Inc. title X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. mimNumber 300382 referenceNumber 2 publisherAbbreviation Wiley pubmedID 11891829 source Ann. Neurol. 51: 340-349, 2002. authors Bonneau, D., Toutain, A., Laquerriere, A., Marret, S., Saugier-Veber, P., Barthez, M.-A., Radi, S., Biran-Mucignat, V., Rodriguez, D., Gelot, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1999&volume=55&issue=3&spage=173 publisherName Blackwell Publishing title Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1. mimNumber 300382 referenceNumber 3 publisherAbbreviation Blackwell pubmedID 10334471 source Clin. Genet. 55: 173-181, 1999. authors Bruyere, H., Lewis, M. E. S., Wood, S., MacLeod, P. 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Neurol. 42: 360-364, 1997. authors Claes, S., Devriendt, K., Lagae, L., Ceulemans, B., Dom, L., Casaer, P., Raeymaekers, P., Cassiman, J.-J., Fryns, J.-P. pubmedImages false title Linkage analysis in three families with nonspecific X-linked mental retardation. mimNumber 300382 referenceNumber 6 pubmedID 8826464 source Am. J. Med. Genet. 64: 137-146, 1996. authors Claes, S., Gu, X. X., Legius, E., Lorenzetti, E., Marynen, P., Fryns, J. P., Cassiman, J. J., Raeymaekers, P. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.a.33753 publisherName John Wiley & Sons, Inc. title Contractions in the second polyA tract of ARX are rare, non-pathogenic polymorphisms. mimNumber 300382 referenceNumber 7 publisherAbbreviation Wiley pubmedID 21204226 source Am. J. Med. Genet. 155A: 164-167, 2011. authors Conti, V., Marini, C., Mei, D., Falchi, M., Ferrari, A. R., Guerrini, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Infantile spasms: case report of sex-linked inheritance. mimNumber 300382 referenceNumber 8 pubmedID 892251 source Dev. Med. Child Neurol. 19: 524-526, 1977. authors Feinberg, A. P., Leahy, W. R. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.10630 publisherName John Wiley & Sons, Inc. title Clinical study and haplotype analysis in two brothers with Partington syndrome. mimNumber 300382 referenceNumber 9 publisherAbbreviation Wiley pubmedID 12376938 source Am. J. Med. Genet. 112: 361-368, 2002. authors Frints, S. G. M., Borghgraef, M., Froyen, G., Marynen, P., Fryns, J.-P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2002&volume=62&issue=6&spage=423 publisherName Blackwell Publishing title X-linked mental retardation: vanishing boundaries between non-specific (MRX) and syndromic (MRXS) forms. mimNumber 300382 referenceNumber 10 publisherAbbreviation Blackwell pubmedID 12485186 source Clin. Genet. 62: 423-432, 2002. authors Frints, S. G. M., Froyen, G., Marynen, P., Fryns, J.-P. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/ajmg.10628 publisherName John Wiley & Sons, Inc. title Re-evaluation of MRX36 family after discovery of an ARX gene mutation reveals mild neurological features of Partington syndrome. mimNumber 300382 referenceNumber 11 publisherAbbreviation Wiley pubmedID 12376949 source Am. J. Med. Genet. 112: 427-428, 2002. authors Frints, S. G. M., Froyen, G., Marynen, P., Willekens, D., Legius, E., Fryns, J.-P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ejhg.2009.139 publisherName Nature Publishing Group title Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C-G/p.Y27X). mimNumber 300382 referenceNumber 12 publisherAbbreviation NPG pubmedID 19738637 source Europ. J. Hum. Genet. 18: 157-162, 2010. authors Fullston, T., Brueton, L., Willis, T., Philip, S., MacPherson, L., Finnis, M., Gecz, J., Morton, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2011&volume=80&issue=6&spage=510 publisherName Blackwell Publishing title Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. mimNumber 300382 referenceNumber 13 publisherAbbreviation Blackwell pubmedID 21496008 source Clin. Genet. 80: 510-522, 2011. authors Fullston, T., Finnis, M., Hackett, A., Hodgson, B., Brueton, L., Baynam, G., Norman, A., Reish, O., Shoubridge, C., Gecz, J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18799476 publisherName HighWire Press title Identification of Arx transcriptional targets in the developing basal forebrain. mimNumber 300382 referenceNumber 14 publisherAbbreviation HighWire pubmedID 18799476 source Hum. Molec. Genet. 17: 3740-3760, 2008. authors Fulp, C. T., Cho, G., Marsh, E. D., Nasrallah, I. M., Labosky, P. A., Golden, J. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0959-437X(06)00064-5 publisherName Elsevier Science title ARX: a gene for all seasons. mimNumber 300382 referenceNumber 15 publisherAbbreviation ES pubmedID 16650978 source Curr. Opin. Genet. 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M., Kremer, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.10310 publisherName John Wiley & Sons, Inc. title Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. mimNumber 300382 referenceNumber 21 publisherAbbreviation Wiley pubmedID 14722918 source Hum. Mutat. 23: 147-159, 2004. authors Kato, M., Das, S., Petras, K., Kitamura, K., Morohashi, K., Abuelo, D. N., Barr, M., Bonneau, D., Brady, A. F., Carpenter, N. J., Cipero, K. 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J. Med. Genet. 110: 410-411, 2002. authors Kleefstra, T., Yntema, H. G., Oudakker, A. R., de Vries, B. B. A., van Bokhoven, H., Hamel, B. C. U., Poppelaars, F. A., Ausems, M. G. E. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.biomedcentral.com/1471-2350/8/25 publisherName BioMed Central title MRX87 family with aristaless X dup24bp mutation and implication for polyalanine expansions. mimNumber 300382 referenceNumber 26 publisherAbbreviation BMC pubmedID 17480217 source BMC Med. Genet. 8: 25, 2007. Note: Electronic Article. authors Laperuta, C., Spizzichino, L., D'Adamo, P., Monfregola, J., Maiorino, A., D'Eustacchio, A., Ventruto, V., Neri, G., D'Urso, M., Chiurazzi, P., Ursini, M. V., Miano, M. G. pubmedImages false publisherUrl http://www.biomedcentral.com/ articleUrl http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19439424 publisherName HighWire Press title Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. mimNumber 300382 referenceNumber 27 publisherAbbreviation HighWire pubmedID 19439424 source Brain 132: 1563-1576, 2009. authors Marsh, E., Fulp, C., Gomez, E., Nasrallah, I., Minarcik, J., Sudi, J., Christian, S. L., Mancini, G., Labosky, P., Dobyns, W., Brooks-Kayal, A., Golden, J. A. pubmedImages false publisherUrl http://highwire.stanford.edu title Expression of a novel aristaless related homeobox gene 'Arx' in the vertebrate telencephalon, diencephalon and floor plate. mimNumber 300382 referenceNumber 28 pubmedID 9256348 source Mech. Dev. 65: 99-109, 1997. authors Miura, H., Yanazawa, M., Kato, K., Kitamura, K. pubmedImages false title X-linked mental retardation with dystonic movements of the hands. mimNumber 300382 referenceNumber 29 pubmedID 3177452 source Am. J. Med. Genet. 30: 251-262, 1988. authors Partington, M. W., Mulley, J. C., Sutherland, G. R., Hockey, A., Thode, A., Turner, G. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2004&volume=66&issue=1&spage=39 publisherName Blackwell Publishing title Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. mimNumber 300382 referenceNumber 30 publisherAbbreviation Blackwell pubmedID 15200506 source Clin. Genet. 66: 39-45, 2004. authors Partington, M. W., Turner, G., Boyle, J., Gecz, J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(12)00591-5 publisherName Elsevier Science title A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. mimNumber 300382 referenceNumber 31 publisherAbbreviation ES pubmedID 23246292 source Am. J. Hum. Genet. 92: 114-125, 2013. authors Poeta, L., Fusco, F., Drongitis, D., Shoubridge, C., Manganelli, G., Filosa, S., Paciolla, M., Courtney, M., Collombat, P., Lioi, M. B., Gecz, J., Ursini, M. V., Miano, M. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s00439-005-0011-2 publisherName Springer title Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation. mimNumber 300382 referenceNumber 32 publisherAbbreviation Springer pubmedID 16078051 source Hum. Genet. 118: 45-48, 2005. authors Poirier, K., Abriol, J., Souville, I., Laroche-Raynaud, C., Beldjord, C., Gilbert, B., Chelly, J., Bienvenu, T. pubmedImages false publisherUrl http://www.springeronline.com/ title New X-linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum. mimNumber 300382 referenceNumber 33 pubmedID 1605226 source Am. J. Med. Genet. 43: 458-466, 1992. authors Proud, V. K., Levine, C., Carpenter, N. J. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.a.32842 publisherName John Wiley & Sons, Inc. title A novel de novo 27 bp duplication of the ARX gene, resulting from postzygotic mosaicism and leading to three severely affected males in two generations. mimNumber 300382 referenceNumber 34 publisherAbbreviation Wiley pubmedID 19606478 source Am. J. Med. Genet. 149A: 1655-1660, 2009. authors Reish, O., Fullston, T., Regev, M., Heyman, E., Gecz, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12177367 publisherName HighWire Press title X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. mimNumber 300382 referenceNumber 35 publisherAbbreviation HighWire pubmedID 12177367 source Neurology 59: 348-356, 2002. authors Scheffer, I. E., Wallace, R. H., Phillips, F. L., Hewson, P., Reardon, K., Parasivam, G., Stromme, P., Berkovic, S. F., Gecz, J., Mulley, J. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(07)00063-8 publisherName Elsevier Science title Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. mimNumber 300382 referenceNumber 36 publisherAbbreviation ES pubmedID 17490853 source Genomics 90: 59-71, 2007. authors Shoubridge, C., Cloosterman, D., Parkinson-Lawerence, E., Brooks, D., Gecz, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/humu.21288 publisherName John Wiley & Sons, Inc. title ARX spectrum disorders: making inroads into the molecular pathology. mimNumber 300382 referenceNumber 37 publisherAbbreviation Wiley pubmedID 20506206 source Hum. Mutat. 31: 889-900, 2010. authors Shoubridge, C., Fullston, T., Gecz, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.biomedcentral.com/1471-2350/6/16 publisherName BioMed Central title XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. mimNumber 300382 referenceNumber 38 publisherAbbreviation BMC pubmedID 15850492 source BMC Med. Genet. 6: 16, 2005. Note: Electronic Article. authors Stepp, M. L., Cason, A. L., Finnis, M., Mangelsdorf, M., Holinski-Feder, E., Macgregor, D., MacMillan, A., Holden, J. J. A., Gecz, J., Stevenson, R. E., Schwartz, C. E. pubmedImages false publisherUrl http://www.biomedcentral.com/ articleUrl http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=12640086 publisherName HighWire Press title Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX. mimNumber 300382 referenceNumber 39 publisherAbbreviation HighWire pubmedID 12640086 source J. Neurol. Neurosurg. Psychiat. 74: 536-538, 2003. authors Stromme, P., Bakke, S. J., Dahl, A., Gecz, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng862 publisherName Nature Publishing Group title Mutations in the human ortholog of aristaless cause X-linked mental retardation and epilepsy. mimNumber 300382 referenceNumber 40 publisherAbbreviation NPG pubmedID 11889467 source Nature Genet. 30: 441-445, 2002. authors Stromme, P., Mangelsdorf, M. E., Shaw, M. A., Lower, K. M., Lewis, S. M. E., Bruyere, H., Lutcherath, V., Gedeon, A. K., Wallace, R. H., Scheffer, I. E., Turner, G., Partington, M., Frints, S. G. M., Fryns, J.-P., Sutherland, G. R., Mulley, J. C., Gecz, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10353782 publisherName HighWire Press title X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11. mimNumber 300382 referenceNumber 41 publisherAbbreviation HighWire pubmedID 10353782 source J. Med. Genet. 36: 374-378, 1999. authors Stromme, P., Sundet, K., Mork, C., Cassiman, J.-J., Fryns, J.-P., Claes, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://thejns.org/doi/abs/10.3171/jns.1972.36.2.0201?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title A morphological classification of sincipital encephalomeningoceles. mimNumber 300382 referenceNumber 42 publisherAbbreviation ATYPON pubmedID 5008734 source J. Neurosurg. 36: 201-211, 1972. authors Suwanwela, C., Suwanwela, N. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=17641262 publisherName HighWire Press title A novel mutation of the ARX gene in a male with nonsyndromic mental retardation. mimNumber 300382 referenceNumber 43 publisherAbbreviation HighWire pubmedID 17641262 source J. Child Neurol. 22: 744-748, 2007. authors Troester, M. M., Trachtenberg, T., Narayanan, V. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.10714 publisherName John Wiley & Sons, Inc. title Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. mimNumber 300382 referenceNumber 44 publisherAbbreviation Wiley pubmedID 12376946 source Am. J. Med. Genet. 112: 405-511, 2002. authors Turner, G., Partington, M., Kerr, B., Mangelsdorf, M., Gecz, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12874405 publisherName HighWire Press title ARX mutations in X-linked lissencephaly with abnormal genitalia. mimNumber 300382 referenceNumber 45 publisherAbbreviation HighWire pubmedID 12874405 source Neurology 61: 232-235, 2003. authors Uyanik, G., Aigner, L., Martin, P., Gross, C., Neumann, D., Marschner-Schafer, H., Hehr, U., Winkler, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2004&volume=65&issue=6&spage=503 publisherName Blackwell Publishing title ARX mutation in a boy with transsphenoidal encephalocele and hypopituitarism. (Letter) mimNumber 300382 referenceNumber 46 publisherAbbreviation Blackwell pubmedID 15151512 source Clin. Genet. 65: 503-505, 2004. authors Van Esch, H., Poirier, K., de Zegher, F., Holvoet, M., Bienvenu, T., Chelly, J., Devriendt, K., Fryns, J.-P. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0303-8467(08)00093-0 publisherName Elsevier Science title Expansion of the ARX spectrum. mimNumber 300382 referenceNumber 47 publisherAbbreviation ES pubmedID 18462864 source Clin. Neurol. Neurosurg. 110: 631-634, 2008. authors Wallerstein, R., Sugalski, R., Cohn, L., Jawetz, R., Friez, M. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:1097716 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 169790795 refSeqAccessionIDs NG_008281.1 dermAtlas false hprdIDs 02307 swissProtIDs Q96QS3 zfinIDs ZDB-GENE-121109-2,ZDB-GENE-990415-15 uniGenes Hs.300304 gtr true cmgGene false ensemblIDs ENSG00000004848,ENST00000379044 umlsIDs C1425272 genbankNucleotideSequences 2212864,20494617,20133936,26013455,211970183,15315599,11085422,211970122,148175295,71517132,511786075,148119784,2642452,148119785,148119786,148119787 geneTests true approvedGeneSymbols ARX geneIDs 170302 proteinSequences 24497589,15315600,119619437,119619438,27923733 geneticsHomeReferenceIDs gene;;ARX;;ARX

entryList

entry status live phenotypeMapList phenotypeMap geneSymbols TAT sequenceID 11280 chromosomeLocationStart 71600753 chromosomeSort 497 phenotypeMimNumber 276600 chromosomeSymbol 16 mimNumber 613018 geneInheritance None phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 276700 phenotypeMappingKey 3 phenotype Tyrosinemia, type II computedCytoLocation 16q22.2 cytoLocation 16q22.1-q22.3 transcript uc002fap.2 chromosomeLocationEnd 71610997 chromosome 16 contributors Ada Hamosh - updated : 10/8/2003 Wilson H. Y. Lo - updated : 2/18/1997 externalLinks cmgGene false mgiHumanDisease true nextGxDx false omiaIDs 001141;;Tyrosinemia, type II coriellDiseases TYR27660;;TYROSINE TRANSAMINASE DEFICIENCY ordrDiseases 3105;;Tyrosinemia type 2 dermAtlas false swissProtIDs P17735 gtr true possumSyndromes 3778;;Tyrosinaemia 2 orphanetDiseases 28378;;8772;;Tyrosinemia type 2 snomedctIDs 124287008,4887000 umlsIDs C0268487 geneTests false geneticAllianceIDs 7282 diseaseOntologyIDs 0050725 geneticsHomeReferenceIDs condition;;tyrosinemia;;tyrosinemia newbornScreeningUrls true clinicalSynopsisExists true mimNumber 276600 dateCreated Wed, 04 Jun 1986 03:00:00 EDT clinicalSynopsis headAndNeckTeethExists false headAndNeckNeckExists false skinNailsHairSkinHistologyExists false oldFormatExists true skinNailsHairSkinExists false miscellaneousExists false headAndNeckEyesExists false abdomenBiliaryTractExists false skinNailsHairExists false headAndNeckMouthExists false genitourinaryBladderExists false skeletalSkullExists false chestDiaphragmExists false neurologicCentralNervousSystemExists false immunologyExists false genitourinaryExists false skeletalPelvisExists false neurologicBehavioralPsychiatricManifestationsExists false molecularBasisExists false growthExists false genitourinaryUretersExists false abdomenGastrointestinalExists false skeletalHandsExists false skeletalExists false skeletalFeetExists false creationDate Undefined genitourinaryExternalGenitaliaFemaleExists false genitourinaryInternalGenitaliaFemaleExists false growthOtherExists false growthWeightExists false laboratoryAbnormalitiesExists false voiceExists false metabolicFeaturesExists false growthHeightExists false endocrineFeaturesExists false skinNailsHairNailsExists false neurologicExists false prenatalManifestationsMovementExists false abdomenSpleenExists false respiratoryExists false hematologyExists false prenatalManifestationsDeliveryExists false skinNailsHairHairExists false prenatalManifestationsPlacentaAndUmbilicalCordExists false genitourinaryInternalGenitaliaMaleExists false genitourinaryExternalGenitaliaMaleExists false headAndNeckExists false neurologicPeripheralNervousSystemExists false cardiovascularHeartExists false editHistory Undefined respiratoryLungExists false abdomenExists false headAndNeckFaceExists false skeletalLimbsExists false cardiovascularExists false cardiovascularVascularExists false headAndNeckHeadExists false abdomenPancreasExists false headAndNeckEarsExists false genitourinaryKidneysExists false respiratoryNasopharynxExists false respiratoryAirwaysExists false skeletalSpineExists false chestRibsSternumClaviclesAndScapulaeExists false neoplasiaExists false abdomenLiverExists false chestBreastsExists false prenatalManifestationsMaternalExists false skinNailsHairSkinElectronMicroscopyExists false inheritanceExists false prenatalManifestationsExists false headAndNeckNoseExists false abdomenExternalFeaturesExists false chestExists false prenatalManifestationsAmnioticFluidExists false respiratoryLarynxExists false chestExternalFeaturesExists false muscleSoftTissueExists false oldFormat Eyes Herpetiform corneal ulcers {HPO HP:0007812}; Neuro Mental retardation {SNOMEDCT:91138005} {UMLS:C0025362} {HPO HP:0001249 UMLS:C0025362,C0423903}; Inheritance Autosomal recessive {SNOMEDCT:258211005} {UMLS:C0441748} {HPO HP:0000007}; Lab Tyrosinemia {SNOMEDCT:190694001} {ICD10CM:E70.21} {UMLS:C0268483} {HPO HP:0003231 UMLS:C0268483}; Tyrosine transaminase deficiency {SNOMEDCT:124287008,4887000} {UMLS:C0268487}; Normal p-hydroxyphenylpyruvic acid oxidase; Normal phenylalanine level; Hydroxyphenylpyruvic aciduria {HPO HP:0003161 UMLS:C0278026}; Soluble tyrosine aminotransferase (TAT) deficiency; Phenylaceticacidemia; Growth Growth retardation {SNOMEDCT:59576002,444896005} {UMLS:C0151686} {HPO HP:0001510 UMLS:C0476243,C0878787}; Skin Painful punctate keratoses of digits, palms, and soles; prefix # titles alternativeTitles RICHNER-HANHART SYNDROME;; TYROSINE AMINOTRANSFERASE DEFICIENCY;; TAT DEFICIENCY;; TYROSINE TRANSAMINASE DEFICIENCY;; KERATOSIS PALMOPLANTARIS WITH CORNEAL DYSTROPHY;; OREGON TYPE TYROSINEMIA;; TYROSINOSIS, OCULOCUTANEOUS TYPE preferredTitle TYROSINEMIA, TYPE II; TYRSN2 phenotypeMapExists true textSectionList textSection textSectionTitle Text textSectionContent A number sign (#) is used with this entry because tyrosinemia type II (TYRSN2) is caused by homozygous or compound heterozygous mutation in the tyrosine aminotransferase gene (TAT; {613018}) on chromosome 16q22. textSectionName text textSectionTitle Description textSectionContent Tyrosinemia type II is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase ({14:Natt et al., 1992}). textSectionName description textSectionTitle Clinical Features textSectionContent {18:Richner (1938)} and {10:Hanhart (1947)} described an oculocutaneous syndrome characterized by herpetiform corneal ulcers and painful punctate keratoses of digits, palms, and soles. {18:Richner (1938)} described skin lesions in brother and sister. Only the brother had corneal lesions. {10:Hanhart (1947)} reported that the parents of this patient were second cousins. {10:Hanhart (1947)} also described associated severe mental and somatic retardation. The pedigree he reported was reproduced by {21:Waardenburg et al. (1961)}. {21:Waardenburg et al. (1961)} described children of a first-cousin marriage, one with the full syndrome and one with only corneal changes. {20:Ventura et al. (1965)} described the syndrome in 2 sons of first-cousin parents. {3:Buist (1967)} referred to studies of a child with tyrosinemia and tyrosine transaminase deficiency, but normal p-hydroxyphenylpyruvic acid oxidase. Phenylalanine level was normal. Hydroxyphenylpyruvic acid was elevated in the urine. {7:Fellman et al. (1969)} reported chemical studies on the same patient. Only the mitochondrial form of tyrosine aminotransferase was present in the liver. The soluble form of tyrosine aminotransferase was lacking. The patient had markedly elevated tyrosine blood levels and an increase in urinary p-hydroxyphenylpyruvate and p-hydroxyphenyllactate. {9:Goldsmith et al. (1973)} demonstrated tyrosinemia and phenylacetic acidemia in this disorder. Their patient was the 14-year-old son of consanguineous Italian parents. The urine contained excessive P-hydroxyphenylactic acid. Urinary P-hydroxyphenylpyruvic acid was normal. Clinical and biochemical improvement accompanied low phenylalanine-low tyrosine diet. They suggested that soluble TAT may be deficient. Mitochondrial tyrosine transaminase was normal. {1:Beinfang et al. (1976)} described the ophthalmologic findings in the patient reported by {9:Goldsmith et al. (1973)}. This condition is also known as tyrosinemia with palmar and plantar keratosis and keratitis. {8:Garibaldi et al. (1977)} observed this disorder, which they called oculocutaneous tyrosinosis, in a 42-month-old girl and her maternal aunt. The parents of the maternal aunt were first cousins. They emphasized the importance of early diagnosis in order to prevent mental retardation by means of a diet restricted in phenylalanine and tyrosine. {11:Hunziker (1980)} reported brother and sister with unusually late onset (about age 15). Their patients' skin lesions were improved with a diet restricted in phenylalanine and tyrosine. In a consanguineous sibship, {17:Rehak et al. (1981)} reported 4 cases of Richner-Hanhart syndrome. Cutaneous manifestations were typical but the eyes were not involved, suggesting heterogeneity in this disorder. {2:Bohnert and Anton-Lamprecht (1982)} reported unique ultrastructural changes: thickening of the granular layer and increased synthesis of tonofibrils and keratohyalin; in the ridged palmar or plantar skin, large numbers of microtubules and unusually tight packing of tonofibrillar masses, which contained tubular channels or inclusions of microtubules. The authors assumed that increased cohesion and tight packing of tonofilaments prevent normal spreading of keratohyalin and result in its globular appearance. Further, they suggested that excessive amounts of intracellular tyrosine enhance crosslinks between aggregated tonofilaments. In an Ashkenazi Jewish family, {5:Chitayat et al. (1992)} observed 2 adult sibs, offspring of a first-cousin marriage, with persistent hypertyrosinemia. A curious feature was that the affected female sib, aged 41 years, had hypertyrosinemia and characteristic oculocutaneous signs; the brother, aged 39 years, had hypertyrosinemia but no oculocutaneous disease. Both sibs had 2 children; none had signs of metabolic fetopathy. {19:Tallab (1996)} described 2 brothers with Richner-Hanhart syndrome from Saudi Arabia. They were sons of consanguineous parents. They showed typical symptoms and signs of the disease. Physical examination revealed patchy hyperkeratotic yellow-white papules and plaques on palms and soles and linear and star-like corneal opacities. Their IQs were 61 and 75. Serum tyrosine levels were markedly elevated with excessive excretion of tyrosine and its metabolites in the urine. A low tyrosine and low phenylalanine diet was given. {4:Cerone et al. (2002)} reported a female patient with tyrosinemia type II who underwent 2 untreated pregnancies. The patient presented at 28 years of age for reevaluation. She was 34 weeks pregnant with a plasma tyrosine of 1302 micro mol/L and phenylalanine of 37 micro mol/L; all other amino acids were within the normal range. Her protein intake ranged from 60 to 90 grams per day. Her first child was evaluated at age 1 year and 4 months. The boy was born at term after an uneventful labor and delivery with a birth weight of 1.9 kg. At 26 months of age he was 66 cm (-3.5 SD), weight was 6.5 kg (-4.3 SD), and head circumference was 43 cm (-2.4 SD). Physical examination showed unremarkable results except for microcephaly and maxillary hypoplasia. Developmental testing indicated a DQ of 72. The second child was evaluated at the age of 12 months with a length of 74 cm (25th percentile), weight of 8.3 kg (3rd percentile), and head circumference of 45 cm (3rd percentile). He also had microcephaly and was not able to walk. Speech delay was also noted. Both children had plasma tyrosine levels in the normal range. The experience from these 2 pregnancies suggested that maternal tyrosinemia has an adverse effect on the developing fetus. textSectionName clinicalFeatures textSectionTitle Cytogenetics textSectionContent In an addendum in proof, {13:Natt et al. (1986)} reported that a patient with multiple congenital anomalies, including tyrosinemia II, showed a small interstitial deletion with breakpoints at 16q22.1 and 16q22.3. {15:Natt et al. (1987)} presented the full report of this patient, who had multiple congenital anomalies and severe mental retardation in addition to typical symptoms of tyrosinemia II. Southern blot analysis using a human TAT cDNA probe showed complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to have been inherited from the mother, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele resulted from a small de novo interstitial deletion, del 16(pter-q22::q22.3-qter), in the chromosome 16 inherited from the father. The haptoglobin locus ({140100}) was codeleted on the chromosome inherited from the father; no HP allele was inherited by the proband from the father. In situ hybridization likewise was consistent with loss of one haptoglobin gene. On the other hand, 2 metallothionein genes, MT1 ({156350}) and MT2 ({156360}), as well as the LCAT gene ({606967}), were not deleted. textSectionName cytogenetics textSectionTitle Diagnosis textSectionContent Prenatal Diagnosis {22:Westphal et al. (1988)} described MspI and HaeIII RFLPs associated with the TAT locus. The authors used the 2 polymorphisms, which have a combined polymorphism information content (PIC) of 0.44, to perform haplotype analysis of the TAT locus in a French family with tyrosinemia type II. The polymorphisms gave a clear delineation of the mutant alleles in each parent and thus provided the opportunity for prenatal diagnosis of this condition in this family. textSectionName diagnosis textSectionTitle Molecular Genetics textSectionContent In patients with tyrosinemia II, {14:Natt et al. (1992)} identified homozygous and compound heterozygous mutations in the TAT gene ({613018.0001}-{613018.0005}). textSectionName molecularGenetics epochCreated 518252400 editHistory carol : 03/26/2014 terry : 11/16/2010 terry : 5/12/2010 terry : 9/17/2009 carol : 9/17/2009 carol : 9/16/2009 terry : 6/9/2005 terry : 4/6/2005 alopez : 3/10/2005 carol : 3/17/2004 cwells : 10/8/2003 carol : 2/11/1999 mark : 2/18/1997 terry : 7/18/1994 davew : 6/29/1994 mimadm : 4/18/1994 warfield : 3/10/1994 carol : 10/16/1992 carol : 7/8/1992 phenotypicSeriesExists true creationDate Victor A. McKusick : 6/4/1986 epochUpdated 1395817200 dateUpdated Wed, 26 Mar 2014 03:00:00 EDT referenceList reference articleUrl http://archopht.ama-assn.org/cgi/pmidlookup?view=long&pmid=180943 publisherName HighWire Press title The Richner-Hanhart syndrome: report of a case with associated tyrosinemia. mimNumber 276600 referenceNumber 1 publisherAbbreviation HighWire pubmedID 180943 source Arch. Ophthal. 94: 1133-1137, 1976. authors Beinfang, D. C., Kuwabara, T., Pueschel, S. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Richner-Hanhart's syndrome: ultrastructural abnormalities of epidermal keratinization indicating a causal relationship to high intracellular tyrosine levels. mimNumber 276600 referenceNumber 2 pubmedID 6124575 source J. Invest. Derm. 79: 68-74, 1982. authors Bohnert, A., Anton-Lamprecht, I. pubmedImages false source New York: McGraw-Hill (pub.) 1967. P. 117. mimNumber 276600 authors Buist, N. title Phenylketonuria and related problems.In: Nyhan, W. L. : Amino Acid Metabolism and Genetic Variation. referenceNumber 3 articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=25&page=317 publisherName Springer title Case report: pregnancy and tyrosinaemia type II. mimNumber 276600 referenceNumber 4 publisherAbbreviation Springer pubmedID 12227462 source J. Inherit. Metab. Dis. 25: 317-318, 2002. authors Cerone, R., Fantasia, A. R., Castellano, E., Moresco, L., Schiaffino, M. C., Gatti, R. pubmedImages false publisherUrl http://www.springeronline.com/ title Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus. mimNumber 276600 referenceNumber 5 pubmedID 1356171 source J. Inherit. Metab. Dis. 15: 198-203, 1992. authors Chitayat, D., Balbul, A., Hani, V., Mamer, O. A., Clow, C., Scriver, C. R. pubmedImages false articleUrl http://archderm.ama-assn.org/cgi/pmidlookup?view=long&pmid=3156564 publisherName HighWire Press title Richner-Hanhart syndrome spares a plantar autograft. mimNumber 276600 referenceNumber 6 publisherAbbreviation HighWire pubmedID 3156564 source Arch. Derm. 121: 539-540, 1985. authors Crovato, F., Desirello, G., Gatti, R., Babbini, N., Rebora, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Soluble and mitochondrial forms of tyrosine aminotransferase: relationship to human tyrosinemia. mimNumber 276600 referenceNumber 7 pubmedID 4389443 source Biochemistry 8: 615-622, 1969. authors Fellman, J. H., Vanbellinghen, P. J., Jones, R. T., Koler, R. D. pubmedImages false title Oculocutaneous tyrosinosis: report of two cases in the same family. mimNumber 276600 referenceNumber 8 pubmedID 33934 source Helv. Paediat. Acta 32: 173-180, 1977. authors Garibaldi, L. R., Siliato, F., De Martini, I., Scarsi, M. R., Romano, C. pubmedImages false title Tyrosinemia with plantar and palmar keratosis and keratitis. mimNumber 276600 referenceNumber 9 pubmedID 4270265 source J. Pediat. 83: 798-805, 1973. authors Goldsmith, L. A., Kang, E. S., Bienfang, D. C., Jimbow, K., Gerald, P. S., Baden, H. P. pubmedImages false title Neue Sonderformen von Keratosis palmo-plantaris, u.a. eine regelmaessig-dominante mit systematisierten Lipomen, ferner 2 einfach-rezessive mit Schwachsinn und z.T. mit Hornhautveraenderungen des Auges (Ektodermatosyndrom). mimNumber 276600 referenceNumber 10 pubmedID 18901242 source Dermatologica 94: 286-308, 1947. authors Hanhart, E. pubmedImages false title Richner-Hanhart syndrome and tyrosinemia type II. mimNumber 276600 referenceNumber 11 pubmedID 6446465 source Dermatologica 160: 180-189, 1980. authors Hunziker, N. pubmedImages false source Pediat. Res. 5: 287-297, 1971. mimNumber 276600 authors Kennaway, N. G., Buist, N. R. M. title Metabolic studies in a patient with hepatic cytosol tyrosine aminotransferase deficiency. referenceNumber 12 title Assignment of the human tyrosine aminotransferase gene to chromosome 16. mimNumber 276600 referenceNumber 13 pubmedID 2870018 source Hum. Genet. 72: 225-228, 1986. authors Natt, E., Kao, F.-T., Rettenmeier, R., Scherer, G. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1357662 publisherName HighWire Press title Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. mimNumber 276600 referenceNumber 14 publisherAbbreviation HighWire pubmedID 1357662 source Proc. Nat. Acad. Sci. 89: 9297-9301, 1992. authors Natt, E., Kida, K., Odievre, M., Di Rocco, M., Scherer, G. pubmedImages false publisherUrl http://highwire.stanford.edu title Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1-q22.3 in a patient with tyrosinemia type II. mimNumber 276600 referenceNumber 15 pubmedID 2891604 source Hum. Genet. 77: 352-358, 1987. authors Natt, E., Westphal, E.-M., Toth-Fejel, S. E., Magenis, R. E., Buist, N. R. M., Rettenmeier, R., Scherer, G. pubmedImages false title Tyrosinemia without liver or renal damage with plantar and palmar keratosis and keratitis (hypertyrosinemia type II). mimNumber 276600 referenceNumber 16 pubmedID 156708 source Helv. Paediat. Acta 34: 177-183, 1979. authors Pelet, B., Antener, I., Faggioni, R., Spahr, A., Gautier, E. pubmedImages false title Richner-Hanhart syndrome (tyrosinaemia-II) (report of four cases without ocular involvement). mimNumber 276600 referenceNumber 17 pubmedID 6453606 source Brit. J. Derm. 104: 469-475, 1981. authors Rehak, A., Selim, M. M., Yadav, G. pubmedImages false source Klin. Monatsbl. Augenheilkd. 100: 580-588, 1938. mimNumber 276600 authors Richner, H. title Hornhautaffektion bei Keratoma palmare et plantare hereditarium. referenceNumber 18 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0190-9622(96)90104-8 publisherName Elsevier Science title Richner-Hanhart syndrome: importance of early diagnosis and early intervention. mimNumber 276600 referenceNumber 19 publisherAbbreviation ES pubmedID 8912606 source J. Am. Acad. Derm. 35: 857-859, 1996. authors Tallab, T.M. pubmedImages false publisherUrl http://www.elsevier.com/ title Cheratomia palmoplantare dissipatum associato a lesioni corneali in due fratelli. mimNumber 276600 referenceNumber 20 pubmedID 5880823 source Boll. Oculist. 44: 497-510, 1965. authors Ventura, G., Biasini, G., Petrozzi, M. pubmedImages false source Springfield, Ill.: Charles C Thomas (pub.) 1961. Pp. 515-517. mimNumber 276600 authors Waardenburg, P. J., Franceschetti, A., Klein, D. title Genetics and Ophthalmology. Vol. 1. referenceNumber 21 title The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II. mimNumber 276600 referenceNumber 22 pubmedID 2456982 source Hum. Genet. 79: 260-264, 1988. authors Westphal, E.-M., Natt, E., Grimm, T., Odievre, M., Scherer, G. pubmedImages false seeAlso Crovato et al. (1985); Kennaway and Buist (1971); Pelet et al. (1979)

entryList

entry status live allelicVariantExists true epochCreated 895474800 geneMap geneSymbols TGIF, HPE4 sequenceID 12294 phenotypeMapList phenotypeMap phenotypeMimNumber 142946 mimNumber 602630 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 236100 phenotypeMappingKey 3 phenotype Holoprosencephaly-4 chromosomeLocationStart 3411924 chromosomeSort 27 chromosomeSymbol 18 mimNumber 602630 geneInheritance None confidence C mappingMethod Ch, A geneName TG-interacting factor mouseMgiID MGI:1194497 mouseGeneSymbol Tgif1 computedCytoLocation 18p11.31 cytoLocation 18p11.3 transcript uc002klz.3 chromosomeLocationEnd 3458408 chromosome 18 contributors Patricia A. Hartz - updated : 09/05/2013 Patricia A. Hartz - updated : 7/29/2010 Victor A. McKusick - updated : 2/23/2007 Patricia A. Hartz - updated : 10/18/2006 Jane Kelly - updated : 5/14/2003 Victor A. McKusick - updated : 1/23/2003 Victor A. McKusick - updated : 5/26/2000 Victor A. McKusick - updated : 12/16/1999 Stylianos E. Antonarakis - updated : 5/11/1999 clinicalSynopsisExists false mimNumber 602630 allelicVariantList allelicVariant status live name HOLOPROSENCEPHALY 4 dbSnps rs121909066 text In a patient with holoprosencephaly-4 ({142946}), {6:Gripp et al. (2000)} identified a C-to-G transversion at nucleotide 83 of the TGIF gene, resulting in a ser28-to-cys substitution immediately preceding the homeodomain. The substitution occurred in a region of TGIF that has transcriptional repression activity. The patient had hypertelorism, congenital nasal pyriform aperture stenosis, a single central incisor, agenesis of the corpus callosum, microcephaly, and developmental delay. The father and paternal grandfather of the patient had ocular hypertelorism, a microsign of holoprosencephaly, and carried the mutation. mutations TGIF, SER28CYS number 1 clinvarAccessions RCV000007394;;1 status live name HOLOPROSENCEPHALY 4 dbSnps rs121909067 text In a patient with holoprosencephaly-4 ({142946}), {6:Gripp et al. (2000)} identified a C-to-G transversion at nucleotide 188 of the TGIF gene, resulting in a pro63-to-arg substitution. The substitution occurred in the linker between alpha helices 1 and 2 of the homeodomain of TGIF. The patient had lobar holoprosencephaly, bilateral cleft lip, central diabetes insipidis, and mental retardation, and was presumably a sporadic case. mutations TGIF, PRO63ARG number 2 clinvarAccessions RCV000007395;;1 status live name HOLOPROSENCEPHALY 4 dbSnps rs121909068 text In a patient with holoprosencephaly-4 ({142946}), {6:Gripp et al. (2000)} identified an A-to-G transition at nucleotide 451 of the TGIF gene, resulting in a thr151-to-ala substitution. The mutation occurred in a region that encodes a domain that binds SMAD2 ({601366}) and HDAC (see HDAC1; {601241}). The patient had semilobar holoprosencephaly, severe microcephaly, hypotelorism, midface hypoplasia, and a midline cleft. The mother did not carry the mutation and the father was unavailable for analysis. Both the phenotypically normal mother and her affected daughter were heterozygous carriers of a 9-bp deletion in the third exon of the SHH gene ({600725.0013}). mutations TGIF, THR151ALA number 3 clinvarAccessions RCV000007396;;1 status live name HOLOPROSENCEPHALY 4 dbSnps rs121909069 text In a patient with holoprosencephaly-4 ({142946}), {6:Gripp et al. (2000)} identified a C-to-T transition at nucleotide 485, resulting in a ser162-to-phe substitution. The mutation occurred in a region that encodes a domain that binds SMAD2 ({601366}) and HDAC (see HDAC1; {601241}). The patient presented with sphenoidal and ethmoidal encephaloceles, agenesis of the corpus callosum, hypertelorism, and a midline cleft. His reportedly normal father also carried the mutation. mutations TGIF, SER162PHE number 4 clinvarAccessions RCV000007397;;1 status live name HOLOPROSENCEPHALY 4 dbSnps rs121909070 text In a female fetus with holoprosencephaly-4 ({142946}) and her father, {1:Aguilella et al. (2003)} identified a tyr59-to-ter (Y59X) mutation caused by a 488C-G transversion in the homeodomain of the TGIF gene. The fetus had a semilobar holoprosencephaly with microcephaly, flat face, hypotelorism, cebocephaly, and turricephaly. Thus she presented a typical form of holoprosencephaly without any visceral malformations. The father presented with mild hypotelorism, lateral cleft lip, and no mental retardation. mutations TGIF, TYR59TER number 5 clinvarAccessions RCV000007398;;1 status live name HOLOPROSENCEPHALY 4 dbSnps rs28939693 text {1:Aguilella et al. (2003)} found a CAG-to-CTG (gln107-to-leu; Q107L) mutation in the N terminus of the HDAC-interacting domain of the TGIF gene in a 35-year-old woman who presented an atypical form of holoprosencephaly-4 ({142946}) with microcephaly, cleft lip and palate, and mild mental retardation. She had a daughter who had died at the age of 18 months from holoprosencephaly. mutations TGIF, GLN107LEU number 6 clinvarAccessions RCV000007399;;1 prefix * titles alternativeTitles TGFB-INDUCED FACTOR;; TG-INTERACTING FACTOR preferredTitle TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR; TGIF textSectionList textSection textSectionTitle Description textSectionContent TGIF belongs to a family of evolutionarily conserved, atypical homeodomain proteins that act as transcriptional repressors and corepressors in retinoid and transforming growth factor (see TGFB, {190180}) signaling pathways ({11:Shen and Walsh, 2005}). textSectionName description textSectionTitle Cloning textSectionContent Retinoic acid receptors (see {180220}) and retinoid X receptors (see {180245}) bind to specific cis-acting retinoid-responsive promoter elements in response to retinoids. By screening a human embryonic liver cDNA expression library to identify factors that specifically interact with the retinoid X receptor responsive element (RXRE) from the rat cellular retinol-binding protein II (RBP2; {180280}) promoter, {2:Bertolino et al. (1995)} recovered cDNAs encoding TGIF. Northern blot analysis revealed that TGIF is expressed as a 2-kb transcript in various tissues. The predicted 272-amino acid TGIF protein belongs to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. The TGIF gene is expressed during early brain development in mice ({3:Bertolino et al., 1996}). {11:Shen and Walsh (2005)} found that Tgif was expressed ubiquitously in the ventricular neuroepithelium of mice on embryonic day (E) 10.5. Tgif displayed a medial to lateral gradient in the developing cerebral cortex at E12.5 and expression quickly declined by E14.5. By EST database analysis and RT-PCR, {7:Hamid et al. (2008)} identified 12 splice variants of human TGIF. All variants contain the 3-prime end of exon 10 and all of exon 11, and they were predicted to encode proteins of 252 to 401 amino acids. Real-time PCR detected highest TGIF expression in adult lung, followed by fetal liver, adult thymus, fetal brain, adult bone marrow, and adult brain. TGIF was also expressed in human hematopoietic cell lines, with highest expression in AML-193, the most highly differentiated cell line. Use of exon-specific primers revealed that variant-4, which contains exon 6 in addition to the common exons, predominated in all tissues and cell lines examined, including primary hematopoietic stem cells. Other TGIF transcripts showed variable expression. textSectionName cloning textSectionTitle Gene Structure textSectionContent {6:Gripp et al. (2000)} found that the TGIF gene contains 4 exons, the last 3 of which contain coding information. {7:Hamid et al. (2008)} determined that the TGIF1 gene contains 11 exons and spans 47.7 kb. The first 9 exons are alternatively spliced, and only exon 11 and the 3-prime portion of exon 10 are common to all splice variants. {7:Hamid et al. (2008)} identified multiple SP1 ({189906})-binding sites and a CpG island upstream of exon 6, which is included in the major splice variant, variant-4. This region was transcriptionally active in reporter gene assays. textSectionName geneStructure textSectionTitle Mapping textSectionContent By FISH analysis, {6:Gripp et al. (2000)} demonstrated that the TGIF gene resides within the HPE4 minimal critical region on chromosome 18. {7:Hamid et al. (2008)} stated that the TGIF1 gene maps to chromosome 18p11.2. textSectionName mapping textSectionTitle Gene Function textSectionContent {2:Bertolino et al. (1995)} found that TGIF can prevent the retinoid X receptor from functioning as a transcriptional activator by interfering with the Rbp2-RXRE. The canonical TGIF binding site contains a TGTCA core sequence located 5-prime to directly repeated AGGTCA half-sites that are recognized by zinc finger-containing nuclear receptors. This binding site is conserved in several RBP2-RXRE-like responsive elements. {14:Wotton et al. (1999)} identified the homeodomain protein TGIF as a SMAD2 (MADH2; {601366})-binding protein and a repressor of transcription. A transforming growth factor-beta (TGFB; see {190180})-activated SMAD complex can recruit TGIF and histone deacetylases (HDACs; see {601241}) to a SMAD target promoter, repressing transcription. Thus, upon entering the nucleus, a SMAD2/SMAD4 (MADH4; {600993}) complex may interact with coactivators, forming a transcriptional activation complex, or with TGIF and HDACs, forming a transcriptional repressor complex. Formation of 1 of these 2 mutually exclusive complexes is determined by the relative levels of SMAD corepressors and coactivators within the cell. TGIF codes for a transcription factor that competitively inhibits binding of the retinoic acid receptor to a retinoid-responsive promoter. Therefore, decreased TGIF levels may lead to enhanced binding of retinoic acid receptor, indicating increased retinoic acid levels. Prenatal exposure to retinoic acid is associated with holoprosencephaly (HPE; see {236100})-like malformations in animal models ({12:Sulik et al., 1995}). In addition, high doses of retinoic acid downregulate Sonic hedgehog (SHH; {600725}) expression in craniofacial primordia in the chicken. Thus, decreased TGIF could result in decreased SHH expression, which could accentuate the effects of an allele of the SHH gene with reduced or no activity. {9:Nanni et al. (1999)} reported that only 10% of patients carrying a TGIF deletion show HPE. Thus, it is possible that either maternal retinoic acid levels or altered activity in another protein could modify the effects of TGIF. {11:Shen and Walsh (2005)} found no direct interaction between Shh and Tgif in mice. Using several mammalian cell lines, {10:Seo et al. (2006)} examined the role of Tgif in Tgfb signaling. They determined that Tgif interacted with c-Jun ({165160}) and the interaction led to the sequestration of Pml ({102578}) to the nucleus and prevented the formation of a functional complex between Pml and Sara (MADHIP; {603755}). Sequestration of Pml further prevented Smad2 phosphorylation, leading to negative regulation of Tgfb signaling. {4:Gongal and Waskiewicz (2008)} showed that Tgif was required for initiation of hindbrain retinoic acid target genes in zebrafish and was involved in hindbrain patterning. Loss of Tgif caused forebrain defects due to decreased downstream Cyp26a1 ({602239}) expression. Overexpression of zebrafish or human TGIF induced ectopic Cyp26a1 expression posterior to its normal domain. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {5:Gripp et al. (1998)} identified 4 missense mutations in the TGIF gene in patients with holoprosencephaly-4 ({142946}); see {602630.0001}-{602630.0004}. In animal models, genes in the Nodal signaling pathway, such as those in the zebrafish mutants 'cyclops,' 'squint,' and 'one-eyed pinhead,' cause HPE. Mice heterozygous for null alleles of both Nodal ({601265}) and Smad2 have cyclopia. Mutation analysis of the TGIF gene in 268 DNA samples of patients with HPE detected 4 heterozygous missense mutations in the coding region, 1 of which was identified in familial HPE and 3 of which were identified in clinically sporadic cases. These mutations affected the transcriptional repression domain of TGIF, the DNA-binding domain, or the domain that interacts with SMAD2, an effector in the NODAL signaling pathway. Several of the mutations caused a loss of TGIF function. {6:Gripp et al. (2000)} concluded that TGIF links the NODAL signaling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures. In 2 families with holoprosencephaly, {9:Nanni et al. (1999)} identified mutations in the TGIF gene in association with mutations in the SHH gene; the form of holoprosencephaly due to mutation in the SHH gene is referred to as holoprosencephaly-3 (HPE3; {142945}). They proposed that the intrafamilial variability in holoprosencephaly may be due to the collaboration of 2 or more unlinked genes, such as SHH and TGIF. {1:Aguilella et al. (2003)} sequenced the TGIF gene of 127 HPE probands. In 2 families presenting a wide range of disease severity, they identified a novel gln107-to-leu mutation (Q107L; {602630.0006}) and what they stated was the first nonsense mutation identified in the TGIF gene, tyr59 to ter (Y59X; {602630.0005}). {8:Lam et al. (2003)} investigated the coding exons of TGIF for mutations in Chinese patients with high myopia. Six SNPs showed a significant difference (P less than 0.05) between patient and control subjects in univariate analysis. Only 657T-G showed statistical significance in the logistic regression model (odds ratio 0.133; 95% CI 0.036-0.488; P = 0.002). Thus, TGIF is a probable candidate gene for high myopia. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {11:Shen and Walsh (2005)} found that Tgif -/- mice with a mixed genetic background were born in approximately mendelian ratios and were indistinguishable from their wildtype littermates. They showed normal growth, behavior, and fertility. Brains were normal in size and weight and all major brain structures appeared normal. Histologic analysis of other major organs showed no discernible pathologic changes. Tgif -/- embryos showed unaltered susceptibility to retinoic acid-induced teratogenic effects. {11:Shen and Walsh (2005)} concluded there may be functional Tgif redundancy in mice, possibly provided by Tgif2 ({607294}). {13:Tateossian et al. (2013)} developed Tgif1 mutant mice on a C57BL/6J genetic background. Tgif1 -/- pups were obtained at less than the mendelian ratio at weaning, and those that survived were smaller and had shorter faces than wildtype littermates. Tgif1 -/- mice developed hearing deficits, with reduced startle response and elevated threshold for auditory-evoked brainstem response, but no obvious abnormalities in the cochlea, organ of Corti, or spiral ganglion neurons were present. By 21 days of age, Tgif1 -/- mice displayed otitis media, and by 2 months, the inflammation had progressed to chronic inflammation with effusion, accompanied by elevated cytokines in ear fluids and suppressed TGF-beta signaling. Pregnant Tgif1 -/- females showed evidence of placental defects. textSectionName animalModel geneMapExists true editHistory mgross : 09/05/2013 alopez : 7/29/2010 terry : 7/29/2010 alopez : 5/5/2010 carol : 3/1/2007 wwang : 3/1/2007 terry : 2/23/2007 carol : 10/31/2006 terry : 10/18/2006 carol : 6/9/2005 cwells : 5/14/2003 carol : 1/29/2003 tkritzer : 1/27/2003 terry : 1/23/2003 mgross : 10/11/2002 cwells : 5/24/2001 mgross : 5/30/2000 mgross : 5/30/2000 mgross : 5/30/2000 mgross : 5/26/2000 mgross : 12/16/1999 mgross : 5/11/1999 psherman : 5/18/1998 dateCreated Mon, 18 May 1998 03:00:00 EDT creationDate Rebekah S. Rasooly : 5/18/1998 epochUpdated 1378364400 dateUpdated Thu, 05 Sep 2013 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1007/s00439-002-0862-8 publisherName Springer title Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. mimNumber 602630 referenceNumber 1 publisherAbbreviation Springer pubmedID 12522553 source Hum. Genet. 112: 131-134, 2003. authors Aguilella, C., Dubourg, C., Attia-Sobol, J., Vigneron, J., Blayau, M., Pasquier, L., Lazaro, L., Odent, S., David, V. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8537382 publisherName HighWire Press title A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif. mimNumber 602630 referenceNumber 2 publisherAbbreviation HighWire pubmedID 8537382 source J. Biol. Chem. 270: 31178-31188, 1995. authors Bertolino, E., Reimund, B., Wildt-Perinic, D., Clerc, R. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1097-0177(199604)205:4<410::AID-AJA5>3.0.CO;2-L publisherName John Wiley & Sons, Inc. title Expression of a novel murine homeobox gene in the developing cerebellar external granular layer during its proliferation. mimNumber 602630 referenceNumber 3 publisherAbbreviation Wiley pubmedID 8901052 source Dev. Dyn. 205: 410-420, 1996. authors Bertolino, E., Wildt, S., Richards, G., Clerc, R. G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17998248 publisherName HighWire Press title Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism. mimNumber 602630 referenceNumber 4 publisherAbbreviation HighWire pubmedID 17998248 source Hum. Molec. Genet. 17: 525-538, 2008. authors Gongal, P. A., Waskiewicz, A. J. pubmedImages false publisherUrl http://highwire.stanford.edu source Am. J. Hum. Genet. 63: A32, 1998. mimNumber 602630 authors Gripp, K. W., Edwards, M. C., Mowat, D., Meinecke, P., Richieri-Costa, A., Zackai, E. H., Elledge, S., Muenke, M. title Mutations in the transcription factor TGIF in holoprosencephaly. (Abstract) referenceNumber 5 articleUrl http://dx.doi.org/10.1038/76074 publisherName Nature Publishing Group title Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. mimNumber 602630 referenceNumber 6 publisherAbbreviation NPG pubmedID 10835638 source Nature Genet. 25: 205-208, 2000. authors Gripp, K. W., Wotton, D., Edwards, M. C., Roessler, E., Ades, L., Meinecke, P., Richieri-Costa, A., Zackai, E. H., Massague, J., Muenke, M., Elledge, S. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1874-9399(08)00090-4 publisherName Elsevier Science title Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. mimNumber 602630 referenceNumber 7 publisherAbbreviation ES pubmedID 18455519 source Biochim. Biophys. Acta 1779: 347-355, 2008. authors Hamid, R., Patterson, J., Brandt, S. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.iovs.org/cgi/pmidlookup?view=long&pmid=12601022 publisherName HighWire Press title TGF-beta-induced factor: a candidate gene for high myopia. mimNumber 602630 referenceNumber 8 publisherAbbreviation HighWire pubmedID 12601022 source Invest. Ophthal. Vis. Sci. 44: 1012-1015, 2003. authors Lam, D. S. C., Lee, W. S., Leung, Y. F., Tam, P. O. I, Fan, D. S. P., Fan, B. J., Pang, C. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10556296 publisherName HighWire Press title The mutational spectrum of the Sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. mimNumber 602630 referenceNumber 9 publisherAbbreviation HighWire pubmedID 10556296 source Hum. Molec. Genet. 8: 2479-2488, 1999. authors Nanni, L., Ming, J. E., Bocian, M., Steinhaus, K., Bianchi, D. W., de Die-Smulders, C., Giannotti, A., Imaizumi, K., Jones, K. L., Del Campo, M., Martin, R. A., Meinecke, P., Pierpont, M. E. M., Robin, N. H., Young, I. D., Roessler, E., Muenke, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(06)00434-5 publisherName Elsevier Science title Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling. mimNumber 602630 referenceNumber 10 publisherAbbreviation ES pubmedID 16916642 source Molec. Cell 23: 547-559, 2006. authors Seo, S. R., Ferrand, N., Faresse, N., Prunier, C., Abecassis, L., Pessah, M., Bourgeade, M.-F., Atfi, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=15831469 publisherName HighWire Press title Targeted disruption of Tgif, the mouse ortholog of a human holoprosencephaly gene, does not result in holoprosencephaly in mice. mimNumber 602630 referenceNumber 11 publisherAbbreviation HighWire pubmedID 15831469 source Molec. Cell. Biol. 25: 3639-3647, 2005. authors Shen, J., Walsh, C. A. pubmedImages false publisherUrl http://highwire.stanford.edu title Teratogenicity of low doses of all-trans retinoic acid in presomite mouse embryos. mimNumber 602630 referenceNumber 12 pubmedID 7502239 source Teratology 51: 398-403, 1995. authors Sulik, K. K., Dehart, D. B., Rogers, J. M., Chernoff, N. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23459932 publisherName HighWire Press title Otitis media in the Tgif knockout mouse implicates TGF-beta signalling in chronic middle ear inflammatory disease. mimNumber 602630 referenceNumber 13 publisherAbbreviation HighWire pubmedID 23459932 source Hum. Molec. Genet. 22: 2553-2565, 2013. authors Tateossian, H., Morse, S., Parker, A., Mburu, P., Warr, N., Acevedo-Arozena, A., Cheeseman, M., Wells, S., Brown, S. D. M. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80712-6 publisherName Elsevier Science title A Smad transcriptional corepressor. mimNumber 602630 referenceNumber 14 publisherAbbreviation ES pubmedID 10199400 source Cell 97: 29-39, 1999. authors Wotton, D., Lo, R. S., Lee, S., Massague, J. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:1194497 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 530424924,530424920,530424922,522838241,28178854,522838245,522838247,522838233,522838232,522838235,522838234,522838236,522838231,522838230 nbkIDs NBK1530;;Holoprosencephaly Overview dermAtlas false hprdIDs 04023 swissProtIDs Q15583 zfinIDs ZDB-GENE-030131-475 uniGenes Hs.373550 refSeqAccessionIDs NG_007447.1 gtr true cmgGene false ensemblIDs ENSG00000177426,ENST00000548489 umlsIDs C1420712 genbankNucleotideSequences 311461905,29243388,311461907,311461909,158255659,311461911,1150425,12654024,30290885,11157990,388973155,10439693,123996150,164691397,8925855,22658433,311461897,311461899,5424649,43430989,47306442,311461901,311461903,74230028,11511182,511791141,527464084,123981319,164689656,1183482,10399792,23369930,21176940,47496612,19205852,62740935,148142312,9180272,28147345,66267020 geneTests true approvedGeneSymbols TGIF1 geneIDs 7050 proteinSequences 311461904,311461906,158255660,311461908,28178857,311461910,530424923,311461912,12654025,28178853,28178855,1150426,522838242,215274200,28178849,28178851,522838246,123996151,4507473,311461898,119622075,22658434,311461900,119622077,119622076,311461902,8925856,123981320,28178845,47496613,522838237,28178843 geneticsHomeReferenceIDs gene;;TGIF1;;TGIF1

entryList

entry status live allelicVariantExists true epochCreated 985680000 geneMap geneSymbols TBX22, CPX, ABERS sequenceID 14769 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 300307 phenotypeInheritance X-linked phenotype ?Abruzzo-Erickson syndrome phenotypeMimNumber 302905 phenotypeMappingKey 3 mimNumber 300307 phenotypeInheritance X-linked phenotype Cleft palate with ankyloglossia phenotypeMimNumber 303400 chromosomeLocationStart 79270254 chromosomeSort 423 chromosomeSymbol X mimNumber 300307 geneInheritance None confidence C mappingMethod REc, Fd geneName T-box 22 comments 1 ABERS family identified with mutation mouseMgiID MGI:2389465 mouseGeneSymbol Tbx22 computedCytoLocation Xq21.1 cytoLocation Xq12-q21 transcript uc004edj.1 chromosomeLocationEnd 79287267 chromosome 23 contributors Marla J. F. O'Neill - updated : 5/9/2013 George E. Tiller - updated : 9/30/2010 Cassandra L. Kniffin - updated : 8/24/2010 Cassandra L. Kniffin - updated : 8/21/2008 Victor A. McKusick - updated : 10/3/2007 George E. Tiller - updated : 3/2/2005 Victor A. McKusick - updated : 5/3/2004 George E. Tiller - updated : 2/16/2004 Ada Hamosh - updated : 9/21/2001 clinicalSynopsisExists false mimNumber 300307 allelicVariantList allelicVariant status live name CLEFT PALATE WITH ANKYLOGLOSSIA text In an Icelandic family segregating cleft palate and ankyloglossia (see CPX; {303400}), {4:Braybrook et al. (2001)} identified a G-to-C transversion at the +1 position of intron 6 of the TBX22 gene. This variant was identified in 21 affected males and 15 carrier females, but not in 39 unaffected sibs, 50 unrelated Icelandic chromosomes, or 200 non-Icelandic chromosomes. Four nonexpressing females were heterozygous for the mutation, which is consistent with previous findings of nonpenetrance in the carrier females of Icelandic (18%) and British Columbia native families (25%). mutations TBX22, IVS6, G-C, +1 number 1 clinvarAccessions RCV000012081;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA dbSnps rs104894943 text In a native kindred from British Columbia, which was one of the first described with cleft palate with ankyloglossia (see {303400}) inherent in mendelian pattern ({3:Bjornsson et al., 1989}), {4:Braybrook et al. (2001)} identified a C-to-T transition in exon 5 of the TBX22 gene at nucleotide 785, resulting in a threonine-to-methionine substitution at codon 260. mutations TBX22, THR260MET number 2 clinvarAccessions RCV000012082;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA dbSnps rs104894944 text In a family with cleft palate with ankyloglossia (see {303400}) from Manitoba, Canada, {4:Braybrook et al. (2001)} identified a G-to-T transversion at nucleotide 359 of the TBX22 gene, resulting in a glycine-to-cysteine substitution at codon 118. The position of the mutation occurs within the T-box domain at the evolutionarily conserved residue found in all other T-box containing genes and may, therefore, result in impaired DNA binding. mutations TBX22, GLY118CYS number 3 clinvarAccessions RCV000012083;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA text In a Brazilian family with cleft palate with ankyloglossia (see {303400}), {4:Braybrook et al. (2001)} identified a G-to-A transition at the exon/intron splice junction GT at intron 4 of the TBX22 gene. In affected individuals from a large 4-generation family with X-linked cleft palate, {7:Marcano et al. (2004)} identified the IVS4+1G-A splice site mutation in the TBX22 gene; the variant was not detected in more than 200 control chromosomes. In the proband of a family segregating X-linked cleft palate, later shown to represent a branch of the family originally studied by {7:Marcano et al. (2004)}, {11:Pauws et al. (2013)} identified the IVS4+1G-A mutation. The proband had a submucous cleft palate, ankyloglossia, speech and language delay, and left-sided eustachian tube dysfunction. His carrier mother had ankyloglossia, which was widely present in the extended family; affected males in the family also had submucous or soft palate cleft. Analysis of RT-PCR products showed that the mutation causes complete abrogation of correct donor splicing in favor of a de novo splice site, which results in generation of an out-of-frame splice product predicted to prematurely terminate if successfully spliced to exon 5. mutations TBX22, IVS4DS, G-A, +1 number 4 clinvarAccessions RCV000012084;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA text In a Brazilian family with cleft palate with ankyloglossia (see {303400}), {4:Braybrook et al. (2001)} identified the deletion of a cytosine at nucleotide 671 of the TBX22 gene, which results in a frameshift introducing a premature termination codon within 4 residues. mutations TBX22, 1-BP DEL, 671C number 5 clinvarAccessions RCV000012085;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA dbSnps rs104894945 text In a family with cleft palate with ankyloglossia (see {303400}), {4:Braybrook et al. (2001)} identified a G-to-T transversion at nucleotide 173 of the TBX22 gene, resulting in conversion of a glutamic acid to a termination codon at residue 56. mutations TBX22, GLU56TER number 6 clinvarAccessions RCV000012086;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA dbSnps rs104894946 text In a 3-generation family with ankyloglossia with or without cleft palate (see {303400}), {5:Braybrook et al. (2002)} identified a T-to-C transition at nucleotide 641 of the TBX22 gene, resulting in conversion of leucine-214 to proline (L214P) in the DNA-binding T-box motif. mutations TBX22, LEU214PRO number 7 clinvarAccessions RCV000012087;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA text In a 4-generation family with ankyloglossia with or without cleft palate (see {303400}), {5:Braybrook et al. (2002)} identified a 3-bp duplication of GCT at nucleotide 583, resulting in insertion of an additional serine residue after serine-194 in the DNA-binding T-box domain. mutations TBX22, 3-BP DUP, 583GCT number 8 clinvarAccessions RCV000012088;;1 status live name CLEFT PALATE WITH ANKYLOGLOSSIA dbSnps rs28935177 text In affected members of a family with ankyloglossia with or without cleft palate (see {303400}), {7:Marcano et al. (2004)} identified a 786A-T transversion in exon 5 of the TBX22 gene, resulting in an asn264-to-tyr (N264Y) mutation. The proband presented with cleft palate only, but the presence of ankyloglossia in the mother suggested the typical semidominant X-linked inheritance of cleft palate. mutations TBX22, ASN264TYR number 9 clinvarAccessions RCV000012089;;1 status live name CLEFT PALATE, X-LINKED text In a Thai girl with a cleft soft palate ({303400}), {12:Suphapeetiporn et al. (2007)} identified a 1-bp deletion (1252delG) in the TBX22 gene, resulting in a frameshift and premature termination. The truncated protein is predicted to retain the T-box domain, but the mutation may result in an unstable mRNA. Her father, who also carried the mutation, had bifid uvula. A paternal uncle reportedly had isolated cleft palate. mutations TBX22, 1-BP DEL, 1252G number 10 clinvarAccessions RCV000012090;;1 status live name ABRUZZO-ERICKSON SYNDROME (1 family) dbSnps rs200060292 text In 2 affected brothers and an affected uncle from a family with Abruzzo-Erickson syndrome (ABERS; {302905}), originally described by {1:Abruzzo and Erickson (1977)}, {11:Pauws et al. (2013)} identified a -5T-A transversion in intron 3 (c.593-5T-A) of the TBX22 gene, within the conserved splice acceptor consensus sequence for exon 4. The mutation was present in heterozygosity in the obligate carrier mother and was not found in the dbSNP database or in 539 control chromosomes. In vitro mRNA splicing assay showed significant reduction in or absence of a 471-bp fragment generated with the wildtype construct when the mutant construct was used. In addition, clonal sequence analysis of RT-PCR products showed that the c.593-5T-A mutation results in a significant increase in the most upstream cryptic splice site product with little wildtype product detected, suggesting that the mutation weakens or abolishes the wildtype acceptor splice site of exon 4. mutations TBX22, IVS3AS, T-A, -5 number 11 clinvarAccessions RCV000043504;;1 prefix * titles preferredTitle T-BOX 22; TBX22 textSectionList textSection textSectionTitle Cloning textSectionContent By in silico analysis using sequence of genomic clones originating from chromosome Xq12-q21, {6:Laugier-Anfossi and Villard (2000)} identified the TBX22 gene. TBX22 encodes a 400-amino acid protein, and the N-terminal region contains a DNA-binding T-box domain that has the unique feature of missing 20 amino acids relative to other known T-box domains. TBX22 transcripts were found exclusively in a human fetal cDNA library. textSectionName cloning textSectionTitle Gene Structure textSectionContent The TBX22 gene contains 7 exons spanning 8.7 kb ({6:Laugier-Anfossi and Villard, 2000}). {2:Andreou et al. (2007)} stated that the TBX22 gene contains 8 coding exons, and they identified a novel noncoding exon, which they called exon 0, located approximately 10 kb upstream of exon 1. The transcriptional start site for exon 0 lies downstream of an active promoter that drives a TBX22 transcript preferentially expressed in human embryonal tissue. textSectionName geneStructure textSectionTitle Mapping textSectionContent The sequence of the TBX22 gene was identified within genomic clone sequences originating from chromosome Xq12-q21 ({6:Laugier-Anfossi and Villard, 2000}). textSectionName mapping textSectionTitle Gene Function textSectionContent {5:Braybrook et al. (2002)} determined that in early human development, TBX22 is expressed in the palatal shelves and is highest prior to elevation to a horizontal position above the tongue. TBX22 mRNA was also detected in the base of the tongue in the region of the frenulum that corresponds to the ankyloglossia seen in CPX patients. The authors identified the orthologous mouse Tbx22 gene, and documented a similar expression pattern in E12.5-E17.5 mouse embryos. {2:Andreou et al. (2007)} found that TBX22 acts as a transcriptional repressor and is capable of autoregulating its expression through the distal TBX22 promoter, similar to TBX5 ({601620}). They presented direct evidence that TBX22 undergoes SUMO1 ({601912}) conjugation and showed that this modification is required for transcriptional repression. The dominant repression domain in TBX22 is located in N-terminal region, which also contains the residue (lysine-63) to which SUMO1 attachment occurs. The TBX22-specific T-box factor-binding element (TBE) is a palindrome based around near-perfect copies of AGGTGTGA. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {4:Braybrook et al. (2001)} identified 6 different mutations, including missense, splice site, and nonsense mutations, in the TBX22 gene in families segregating X-linked cleft palate and ankyloglossia (see CPX; {303400}). {5:Braybrook et al. (2002)} reported 2 additional familial cases of cleft palate with ankyloglossia with novel missense and insertion mutations ({300307.0007} and {300307.0008}), each occurring within the DNA-binding T-box domain. {7:Marcano et al. (2004)} performed analysis of the TBX22 gene in a large sample of patients with cleft palate with no preselection for inheritance or ankyloglossia. They found coding mutations in 5 of 200 patients in North American and Brazilian cohorts, with an additional 4 putative splice site mutations. They also identified mutations in previously unreported CPX families and presented a combined genotype/phenotype analysis of previously reported familial cases. Males frequently exhibited cleft palate and ankyloglossia together (78%), as did a smaller percentage of carrier females. Mutations within families could result in either cleft palate only, ankyloglossia only, or both, indicating that these defects are distinct parts of the phenotypic spectrum. To investigate their effects on DNA binding, subcellular localization, and transcriptional activity, {2:Andreou et al. (2007)} studied 10 different missense mutations that are phenotypically equivalent to loss-of-function alleles. DNA binding assays indicated that missense mutations at or near predicted contact points with the DNA backbone compromise stable DNA-protein interactions. The authors showed that TBX22 functions as a transcriptional repressor and that TBX22 missense mutations result in impaired repression activity. No effect on nuclear localization of TBX22 was observed. {2:Andreou et al. (2007)} found that TBX22 is a target for the small ubiquitin-like modifier SUMO1 ({601912}) and that this modification is required for TBX22 repressor activity. (Disruption of the SUMO1 gene causes orofacial cleft ({601912.0001}).) Although the site of SUMO attachment at lysine-63 is upstream of the T-box domain, loss of SUMO1 modification is consistently found in all pathogenic X-linked cleft palate missense mutations. This implied a general mechanism linking the loss of SUMO conjugation to the loss of TBX22 function. Orofacial clefts are well known for their complex etiology and variable penetrance, involving both genetic and environmental risk factors. The sumoylation process is also subject to and profoundly affected by similar environmental stresses. Thus, {2:Andreou et al. (2007)} suggested that SUMO modification may represent a common pathway that regulates normal craniofacial development and is involved in the pathogenesis of both mendelian and idiopathic forms of orofacial clefting. Among 53 unrelated Thai patients with nonsyndromic cleft palate, {12:Suphapeetiporn et al. (2007)} identified 4 patients, each with a different potentially pathogenic mutation in the TBX22 gene (see, e.g., {300307.0010}). Two of the patients were found to have a family history of the disorder. The authors concluded that TBX22 mutations are a cause of nonsyndromic isolated cleft palate in the Thai population. Among 80 patients with isolated cleft palate, 57 with cleft palate/ankyloglossia, and 295 controls, {10:Pauws et al. (2009)} found a significant association between 2 SNPs in the promoter region of the TBX22 gene and cleft palate with ankyloglossia: the -575A allele of {dbSNP rs7055763} conferred an odds ratio (OR) of 5.3 (p = 5.6 x 10(-6)) and the -144A allele of {dbSNP rs41307258} conferred an OR of 6.2 (p = 1.8 x 10(-5)). There was no significant association between these SNPs and isolated cleft palate. {10:Pauws et al. (2009)} identified 4 promoter region haplotypes, only 1 of which was associated with cleft palate with ankyloglossia. Functional expression studies showed that the risk haplotype, which included the -144A allele of {dbSNP rs41307258}, resulted in decreased promoter activity of about 45%. {10:Pauws et al. (2009)} suggested that this risk haplotype, in concert with additional genetic and/or environmental factors, may contribute to phenotypic variation and provide a novel causative mechanism for cleft palate, especially in patients with ankyloglossia. In a family with the CHARGE-like Abruzzo-Erickson syndrome (ABERS; {302905}), {11:Pauws et al. (2013)} analyzed the candidate gene TBX22 and identified an intronic sequence variant ({300307.0011}) that segregated with the disease and was not found in the dbSNP database or in 539 control chromosomes. Screening of new patients with classic X-linked cleft palate phenotypes identified 2 splice site mutations in unrelated patients (see, e.g., {300307.0004}). Reviews {8:Packham and Brook (2003)} reviewed the human disorders that have been linked to mutations in T-box genes: Holt-Oram syndrome (HOS; {142900}), ulnar-mammary syndrome (UMS; {181450}), DiGeorge syndrome (DGS; {188400}), ACTH deficiency ({201400}), and cleft palate with ankyloglossia. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {9:Pauws et al. (2009)} generated a Tbx22-null mouse, which demonstrated a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. There was also persistence of the oronasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Oronasal defects led to postnatal lethality in about 50% of Tbx-null mice. There was a marked reduction in intramembranous bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Ossification was severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. {9:Pauws et al. (2009)} suggested that Tbx22 may play an important role in the osteogenic patterning of the posterior hard palate, rather than having a major role in palatal shelf closure. textSectionName animalModel geneMapExists true editHistory carol : 09/11/2013 carol : 5/9/2013 carol : 5/9/2013 terry : 11/6/2012 wwang : 10/15/2010 terry : 9/30/2010 wwang : 9/7/2010 ckniffin : 8/24/2010 ckniffin : 8/24/2010 wwang : 9/2/2008 ckniffin : 8/21/2008 alopez : 10/5/2007 alopez : 10/5/2007 terry : 10/3/2007 alopez : 3/2/2005 tkritzer : 6/21/2004 tkritzer : 5/12/2004 terry : 5/3/2004 cwells : 2/16/2004 alopez : 10/15/2001 alopez : 9/21/2001 terry : 9/21/2001 carol : 3/28/2001 dateCreated Tue, 27 Mar 2001 03:00:00 EST creationDate Carol A. Bocchini : 3/27/2001 epochUpdated 1378882800 dateUpdated Wed, 11 Sep 2013 03:00:00 EDT referenceList reference articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=839509 publisherName HighWire Press title A new syndrome of cleft palate associated with coloboma, hypospadias, deafness, short stature, and radial synostosis. mimNumber 300307 referenceNumber 1 publisherAbbreviation HighWire pubmedID 839509 source J. Med. Genet. 14: 76-80, 1977. authors Abruzzo, M. A., Erickson, R. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63047-X publisherName Elsevier Science title TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. mimNumber 300307 referenceNumber 2 publisherAbbreviation ES pubmedID 17846996 source Am. J. Hum. Genet. 81: 700-712, 2007. authors Andreou, A. M., Pauws, E., Jones, M. C., Singh, M. K., Bussen, M., Doudney, K., Moore, G. E., Kispert, A., Brosens, J. J., Stanier, P. pubmedImages false publisherUrl http://www.elsevier.com/ title X-linked cleft palate and ankyloglossia in an Icelandic family. mimNumber 300307 referenceNumber 3 pubmedID 2563678 source Cleft Palate J. 26: 3-8, 1989. authors Bjornsson, A., Arnason, A., Tippet, P. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng730 publisherName Nature Publishing Group title The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. mimNumber 300307 referenceNumber 4 publisherAbbreviation NPG pubmedID 11559848 source Nature Genet. 29: 179-183, 2001. authors Braybrook, C., Doudney, K., Marcano, A. C. B., Arnason, A., Bjornsson, A., Patton, M. A., Goodfellow, P. J., Moore, G. E., Stanier, P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12374769 publisherName HighWire Press title Craniofacial expression of human and murine TBX22 correlates with the cleft palate and ankyloglossia phenotype observed in CPX patients. mimNumber 300307 referenceNumber 5 publisherAbbreviation HighWire pubmedID 12374769 source Hum. Molec. Genet. 11: 2793-2804, 2002. authors Braybrook, C., Lisgo, S., Doudney, K., Henderson, D., Marcano, A. C. B., Strachan, T., Patton, M. A., Villard, L., Moore, G. E., Stanier, P., Lindsay, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0378-1119(00)00326-7 publisherName Elsevier Science title Molecular characterization of a new human T-box gene (TBX22) located in Xq21.1 encoding a protein containing a truncated T-domain. mimNumber 300307 referenceNumber 6 publisherAbbreviation ES pubmedID 11024289 source Gene 255: 289-296, 2000. authors Laugier-Anfossi, F., Villard, L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=14729838 publisherName HighWire Press title TBX22 mutations are a frequent cause of cleft palate. mimNumber 300307 referenceNumber 7 publisherAbbreviation HighWire pubmedID 14729838 source J. Med. Genet. 41: 68-74, 2004. authors Marcano, A. C. B., Doudney, K., Braybrook, C., Squires, R., Patton, M. A., Lees, M. M., Richieri-Costa, A., Lidral, A. C., Murray, J. C., Moore, G. E., Stanier, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12668595 publisherName HighWire Press title T-box genes in human disorders. mimNumber 300307 referenceNumber 8 publisherAbbreviation HighWire pubmedID 12668595 source Hum. Molec. Genet. 12(R1): R37-R44, 2003. authors Packham, E. A., Brook, J. D. pubmedImages false publisherUrl http://highwire.stanford.edu title Tbx22(null) mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes. mimNumber 300307 referenceNumber 9 pubmedID 19648291 source Hum. Molec. Genet. 18: 4171-4179, 2009. Note: Erratum: Hum. Molec. Genet. 19: 3103 only, 2010. authors Pauws, E., Hoshino, A., Bentley, L., Prajapati, S., Keller, C., Hammond, P., Martinez-Barbera, J.-P., Moore, G. E., Stanier, P. pubmedImages false title A functional haplotype variant in the TBX22 promoter is associated with cleft palate and ankyloglossia. (Letter) mimNumber 300307 referenceNumber 10 pubmedID 19648124 source J. Med. Genet. 46: 555-561, 2009. authors Pauws, E., Moore, G. E., Stanier, P. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2013&volume=83&issue=4&spage=352 publisherName Blackwell Publishing title X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations. mimNumber 300307 referenceNumber 11 publisherAbbreviation Blackwell pubmedID 22784330 source Clin. Genet. 83: 352-358, 2013. authors Pauws, E., Peskett, E., Boissin, C., Hoshino, A., Mengrelis, K., Carta, E., Abruzzo, M. A., Lees, M., Moore, G. E., Erickson, R. P., Stanier, P. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2007&volume=72&issue=5&spage=478 publisherName Blackwell Publishing title TBX22 mutations are a frequent cause of non-syndromic cleft palate in the Thai population. mimNumber 300307 referenceNumber 12 publisherAbbreviation Blackwell pubmedID 17868388 source Clin. Genet. 72: 478-483, 2007. authors Suphapeetiporn, K., Tongkobpetch, S., Siriwan, P., Shotelersuk, V. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ externalLinks mgiIDs MGI:2389465 mgiHumanDisease false ncbiReferenceSequences 530422061,530422063,530422059,158187508,158187510,40316908 refSeqAccessionIDs NG_008998.1 dermAtlas false hprdIDs 02253 swissProtIDs Q9Y458 zfinIDs ZDB-GENE-090626-2 uniGenes Hs.374253 gtr true cmgGene false ensemblIDs ENSG00000122145,ENST00000373296 umlsIDs C1420611 genbankNucleotideSequences 325463236,21757304,3334727,16356684,10834637,148143085,511785290,227935066,227935067,40225960,92178179,74230034 geneTests true approvedGeneSymbols TBX22 geneIDs 50945 proteinSequences 325463237,578840712,227935068,578840714,10834638,18375603,28381405,40225961,530422064,578840717,578840719,530422060,119618995,578838386,119618994,530422062,16356685,158187509,158187511,193783569 nextGxDx true locusSpecificDBs http://www.LOVD.nl/TBX22;;TBX22 database at LOVD

entryList

entry status live allelicVariantExists true epochCreated 518252400 geneMap geneSymbols BTK, AGMX1, IMD1, XLA, AT sequenceID 14803 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 300300 phenotypeInheritance X-linked recessive phenotype Agammaglobulinemia and isolated hormone deficiency phenotypeMimNumber 307200 phenotypeMimNumber 300755 mimNumber 300300 phenotypeInheritance X-linked recessive phenotypicSeriesMimNumber 601495 phenotypeMappingKey 3 phenotype Agammaglobulinemia, X-linked 1 chromosomeLocationStart 100604434 chromosomeSort 457 chromosomeSymbol X mimNumber 300300 geneInheritance None confidence C mappingMethod H, Fd, A geneName Bruton agammaglobulinemia tyrosine kinase mouseMgiID MGI:88216 mouseGeneSymbol Btk computedCytoLocation Xq22.1 cytoLocation Xq21.3-q22 transcript uc004ehg.2 chromosomeLocationEnd 100641211 chromosome 23 contributors Patricia A. Hartz - updated : 2/2/2009 Paul J. Converse - updated : 11/21/2008 Cassandra L. Kniffin - updated : 10/13/2008 Patricia A. Hartz - updated : 5/2/2008 Cassandra L. Kniffin - updated : 3/21/2007 Paul J. Converse - updated : 4/11/2006 Patricia A. Hartz - updated : 3/27/2006 Victor A. McKusick - updated : 1/15/2004 Paul J. Converse - updated : 1/25/2002 Paul J. Converse - updated : 1/9/2002 Victor A. McKusick - updated : 10/30/2001 Deborah L. Stone - updated : 10/19/2001 Victor A. McKusick - updated : 3/13/2001 Victor A. McKusick - updated : 2/23/2000 Victor A. McKusick - updated : 9/23/1999 Victor A. McKusick - updated : 5/14/1999 Victor A. McKusick - updated : 5/15/1998 Victor A. McKusick - updated : 6/18/1997 Victor A. McKusick - updated : 2/12/1997 Moyra Smith - updated : 8/29/1996 Moyra Smith - updated : 3/13/1996 externalLinks cmgGene false mgiHumanDisease false hprdIDs 02248 nbkIDs NBK1453;;X-Linked Agammaglobulinemia refSeqAccessionIDs NG_009616.1 uniGenes Hs.733206,Hs.159494 approvedGeneSymbols BTK nextGxDx true locusSpecificDBs http://structure.bmc.lu.se/idbase/BTKbase/;;BTK base: Mutation registry for X-linked agammaglobulinemia;;;http://www.LOVD.nl/BTK;;BTK database at LOVD dermAtlas false umlsIDs C1412841 gtr true geneIDs 695 coriellDiseases AGA30030;;BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK swissProtIDs Q06187 zfinIDs ZDB-GENE-070531-1 ensemblIDs ENSG00000010671,ENST00000308731 geneTests true mgiIDs MGI:88216 ncbiReferenceSequences 530433292,213385292,530422151 ordrDiseases 1033;;Bruton type agammaglobulinemia genbankNucleotideSequences 16552691,83483894,76057624,2281904,76057626,76057628,7381349,76057630,312466,575888,80860361,110624012,76057620,76057622,13556817,148147188,76057640,148147189,76057642,148147185,148147186,148147187,76057632,76057634,76057636,164697727,76057638,62147590,62147584,62147586,10850590,62147592,106876444,5263001,62147582,7157920,7157922,80478104,80478109,511785064,1226232,164690234,7157916,7157918,7157912,632958,7157914,7157908,7157910,545560959,71515454,7157904,7157906 proteinSequences 545560960,4557377,632960,62147583,7157921,7157923,76057625,80478105,76057627,76057629,80478110,7381350,76057631,312467,575890,76057621,76057623,76057641,76057643,189067298,547759,76057633,76057635,193787041,76057637,1684918,76057639,7157917,565324227,7157919,62147591,565324225,7157913,62147585,7157915,62147587,7157909,517438,7157911,119623261,7157905,62147593,119623263,7157907,119623262 geneticsHomeReferenceIDs gene;;BTK;;BTK clinicalSynopsisExists false mimNumber 300300 allelicVariantList allelicVariant status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620183 text In a patient with X-linked agammaglobulinemia ({300755}), {46:Vetrie et al. (1993)} identified a G-to-A transition at nucleotide 1706, resulting in a change of arginine-525 to glutamine. This conserved amino acid substitution was predicted to have a highly detrimental effect on the catalytic function of the putative protein-tyrosine kinase. Loss of the conserved arg525 could prevent substrate recognition because this residue is thought to be important in the substrate-specific domain. {32:Ohta et al. (1994)} also described the arg525-to-gln mutation in a family in which the diagnosis of common variable immunodeficiency disease had been made. mutations BTK, ARG525GLN number 1 clinvarAccessions RCV000012095;;2 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620184 text In a patient with X-linked agammaglobulinemia ({300755}), {46:Vetrie et al. (1993)} identified an A-to-G transition at position 1420, resulting in a substitution of glutamic acid for lysine-430. Substitution of lys430 (equivalent to lys295 of v-src) within the ATP-binding site would completely abolish kinase activity. mutations BTK, LYS430GLU number 2 clinvarAccessions RCV000012096;;1 status live name HYPOAGAMMAGLOBULINEMIA, X-LINKED dbSnps rs28935478 text Like most other cytoplasmic tyrosine kinases, the Bruton tyrosine kinase contains a unique amino terminal region, SH3 and SH2 domains (short for SRC homology 3 and 2, respectively), and a carboxy-terminal kinase domain. In a patient with atypical X-linked agammaglobulinemia ({300755}), {37:Saffran et al. (1994)} found a point mutation in the SH2 domain of BTK in a B-cell line. SH2 domains are critical mediators of binding with phosphotyrosine-containing proteins in the cell. The mutation was located in what crystal-structure studies of the SRC SH2 domain predict is a critical hydrophobic binding pocket. The consequence of this mutation is predicted to be decreased stability of the BTK protein, possibly resulting from the inability of BTK to interact with important substrates. The patient was a 23-year-old man who was the oldest of 3 brothers previously described as having atypical X-linked agammaglobulinemia by {10:Conley and Puck (1988)}. A diagnosis of hypogammaglobulinemia was made when the proband was 6 years old and his brothers were 5 and 2 years old. Without therapy, the patient's serum IgG concentration was 590 mg per deciliter. All 3 brothers had 0.3 to 2% B cells in the peripheral circulation, whereas patients with typical Bruton agammaglobulinemia have a mean of 0.1% and normal subjects have 5 to 15% B cells. Although the patient complied poorly with therapy, he had not had serious infections. The single point mutation found in the SH2 domain of the coding sequence changed amino acid residue 361 from tyrosine to cysteine as a result of a TAC-to-TGC transition. {3:Buckley (1994)}, who provided a diagram of the structure of the BTK protein, suggested that some of the other less severe antibody-deficiency syndromes in humans could be caused by mutations in the non-kinase portions of the BTK gene. In addition, she pointed with interest to the fact that BTK is also expressed in cells of the myeloid lineage and that it is well known that intermittent neutropenia occurs in boys with X-linked agammaglobulinemia, particularly at the height of an acute infection ({4:Buckley and Rowlands, 1973}). She raised the possibility that BTK is only one of the signaling molecules in myeloid maturation and that neutropenia may develop in X-linked agammaglobulinemia only when white cell production is rapid. In a patient with mild X-linked agammaglobulinemia, {8:Conley et al. (1994)} identified an A-to-G transition in exon 12, resulting in a substitution of cysteine for tyrosine-361. mutations BTK, TYR361CYS number 3 clinvarAccessions RCV000012099;;1 status live name ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III text In a sporadic case of the syndrome of X-linked agammaglobulinemia and isolated growth hormone deficiency ({307200}), {15:Duriez et al. (1994)} analyzed the BTK gene by RT-PCR, sequencing of cDNA and genomic DNA, and in vitro splicing assays to demonstrate an intronic point mutation, 1882+5G-A, located in the tyrosine kinase domain. This exon-skipping event resulted in a frameshift leading to a premature stop codon 14 amino acids downstream and in the loss of the last 61 residues of the carboxy-terminal end of the protein. The possibility that a mutant form of BTK may give rise to XLA alone in most cases but that some mutant forms can generate both XLA and IGHD suggests that the BTK gene is expressed in the pituitary gland. To test this hypothesis, {15:Duriez et al. (1994)} carried out 30 cycles of RT-PCR on mRNA from pituitaries, and the product was sequenced. This led to the detection of a specific BTK amplification product of expected size and sequence. The finding tempted {15:Duriez et al. (1994)} to speculate that the protein tyrosine kinase encoded by the BTK gene plays a role in the biosynthesis or secretion of growth hormone and that some mutant forms of the BTK protein can impair both the production of growth hormone and the development of B lineage cells. They stated that 'characterisation of additional BTK gene mutations in the rare patients inheriting both XLA and IGHD is eagerly awaited.' mutations BTK, IVS17DS, G-A, +5 number 4 clinvarAccessions RCV000012100;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620185 text {32:Ohta et al. (1994)} described cases of X-linked agammaglobulinemia ({300755}) with a G-to-A transition at nucleotide 215 resulting in an arg28-to-his (R28H) amino acid replacement. The same amino acid change occurs as the cause of xid in the mouse but the mutation is a C-to-T transition at nucleotide 214. The arg28-to-his mutation was described in a case of XLA by {13:de Weers et al. (1994)}. {54:Wood et al. (2001)} found the R28H mutation in a 25-year-old man with a selective antipolysaccharide antibody deficiency whose IgG levels had fallen slightly below the normal range since the age of 23 years but who had remained well on antibiotic prophylaxis for 12 years. The authors suggested that male patients with antipolysaccharide antibody deficiency should be evaluated for B-cell lymphopenia and BTK mutations. mutations BTK, ARG28HIS number 5 clinvarAccessions RCV000012101;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620186 text There is little concordance of phenotype with genotype in XLA ({300755}) and defects in BTK cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. {5:Bykowsky et al. (1996)} described 2 brothers with a T-to-C transition of nucleotide 134 that resulted in change of the translation initiation ATG (met) to ACG (thr). The brothers had different clinical and laboratory phenotypes. The proband lacked immunoglobulins and B cells and had recurrent infections, whereas his older affected brother had normal levels of IgG and IgM and very few infections. Both had undetectable levels of BTK kinase activity in circulating mononuclear cells. Complete sequencing of the BTK gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. mutations BTK, MET1THR number 6 clinvarAccessions RCV000012102;;1 status live name HYPOGAMMAGLOBULINEMIA, X-LINKED text {22:Jones et al. (1996)} described 3 brothers affected by immunodeficiency characterized by low B cell numbers and hypogammaglobulinemia ({300755}), but normal T cell numbers and function. One brother presented at the age of 2 years with pneumococcal pneumonia and empyema requiring thoracotomy. He had a history of recurrent chest infections and severe otitis media. He developed pneumococcal meningitis at 5 years, at which time the diagnosis of hypogammaglobulinemia was first made. The second brother presented at the age of 2 years with a cervical abscess, followed several months later by an episode of pneumococcal meningitis. At 3 years he developed pneumococcal pericarditis requiring pericardiectomy. This occurred concurrently with his elder brother's pneumococcal meningitis, and as a result both boys were investigated and found to have hypogammaglobulinemia. Both boys received routine immunizations as well as Pneumovax. The third brother was identified by screening at the age of 8 weeks because of immunodeficiency in the older brothers. None of the brothers had received regular immunoglobulin replacement treatment. Analysis of cDNA prepared from the 3 affected brothers identified a single nucleotide alteration (C-to-A) at nucleotide 1952 (1952C-A). This resulted in a nonpolar-to-polar amino acid substitution (alanine to aspartic acid) in the kinase domain near the C-terminal end of the BTK protein. mutations BTK, ALA-ASP, 1952C-A number 7 clinvarAccessions RCV000012103;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620187 text In 2 patients with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a C-to-T transition at a CpG dinucleotide in exon 2, resulting in a stop codon at position 13 and a truncated protein. mutations BTK, ARG13TER number 8 clinvarAccessions RCV000012097;;2 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620188 text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a C-to-T transition at a CpG dinucleotide in exon 2, resulting in a stop codon at position 15 and a truncated protein. mutations BTK, GLN15TER number 9 clinvarAccessions RCV000012098;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128620189 text In 2 patients with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified an A-to-C transition at position 229, resulting in a substitution of proline for threonine-33. This mutation was found in the pleckstrin homology domain. mutations BTK, THR33PRO number 10 clinvarAccessions RCV000012104;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 4-bp (GAAA) deletion at codons 76 and 77 in exon 3, resulting in a frameshift and a premature stop codon at position 120. mutations BTK, 4-BP DEL, CODON 76, GAAA number 11 clinvarAccessions RCV000012105;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {16:Hagemann et al. (1994)} identified a 2-bp deletion at the 5-prime end of intron 2. Two adenines were deleted from positions +3 and +4 of the consensus sequence GTAAGT at the donor splice site. Although the deletion does not break the GT/AG boundary rule, the resulting donor splice site does not match the consensus sequence, and the mutation would most likely result in exon 2 skipping. This would remove the 5-prime end of the coding sequence, including the translation start site and the PH domain. mutations BTK, 2-BP DEL, IVS2DS, +3AA number 12 clinvarAccessions RCV000012106;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {16:Hagemann et al. (1994)} identified a G-to-C substitution, which is the first nucleotide of the acceptor splice site of intron 4, that breaks the GT/AG exon-intron boundary rule. The skipping of exon 5 would cause a frameshift. mutations BTK, IVS4AS, G-C, -1 number 13 clinvarAccessions RCV000012107;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {2:Bradley et al. (1994)} identified a 21-bp insertion at position 442 in the 5-prime terminal region, resulting in an in-frame insertion of 7 amino acids (ser-val-phe-ser-ser-thr-arg) between amino acids 103 and 104 in the protein. {16:Hagemann et al. (1994)} found that the inserted sequence matched the 3-prime acceptor sequence of intron 4 except for an A-to-G transition at position -2 from the 3-prime end. This base substitution breaks the GT/AG boundary rule. An alternative splice site 22-bp upstream of the normal 3-prime intron boundary matches the AG acceptor consensus sequence and would explain the 21-bp inserted sequence from the patient's cDNA. mutations BTK, 21-BP INS, NT442 number 14 clinvarAccessions RCV000012108;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621190 text In a patient with severe X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a T-to-A transition in exon 5, resulting in a substitution of aspartic acid for valine-113 in the pleckstrin homology domain. This patient was below the fifth percentile in height, but when evaluated for growth hormone deficiency, was found to have normal growth hormone production. It is possible that other genetic or environmental factors, in concert with absent or defective Btk, cause growth hormone deficiency. mutations BTK, VAL113ASP number 15 clinvarAccessions RCV000012109;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 1-bp (A) deletion at codon 130 in exon 5, resulting in a frameshift. mutations BTK, 1-BP DEL, CODON 130, A number 16 clinvarAccessions RCV000012110;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 1-bp (A) insertion at codon 186 in exon 7, resulting in a frameshift. mutations BTK, 1-BP INS, CODON 186, A number 17 clinvarAccessions RCV000012111;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {13:de Weers et al. (1994)} identified an 8-bp (CTACATAG) insertion at position A721 in the N-terminal region, resulting in a frameshift and a truncated protein. mutations BTK, 8-BP INS, NT721 number 18 clinvarAccessions RCV000012112;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 1-bp (A) deletion at codon 218 in exon 8, resulting in a frameshift. mutations BTK, 1-BP DEL, CODON 218, A number 19 clinvarAccessions RCV000012113;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621191 text In a patient with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a G-to-T transition, resulting in a stop codon at position 240 and a truncated protein. This mutation was found in the SH3 domain. mutations BTK, GLU240TER number 20 clinvarAccessions RCV000012114;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621192 text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a G-to-A transition in exon 8, resulting in a stop codon at position 252 and a truncated protein. This mutation was found in the SH3 domain. mutations BTK, TRP252TER number 21 clinvarAccessions RCV000012115;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621193 text In a patient with X-linked agammaglobulinemia ({300755}), {2:Bradley et al. (1994)} identified a C-to-T transition at position 895, resulting in a stop codon at position 255 and a severely truncated protein lacking the remaining 404 amino acids, which include the SH2 and kinase domains. This patient and his brother have no detectable B-cells, confirming that the absence of the functional domains of Btk results in a classic XLA phenotype. mutations BTK, ARG255TER number 22 clinvarAccessions RCV000012116;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In 2 patients with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a G-to-A substitution at nucleotide 909, which is the first nucleotide of the donor splice site of intron 9. The mutation causes a deletion of 21 amino acids between residues gln260 and glu280 due to skipping of exon 9. This mutation was found in the SH3 domain. mutations BTK, IVS9DS, G-A, +1 number 23 clinvarAccessions RCV000012117;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 1-bp (G) deletion associated with a 3-bp (TTA) insertion at codon 261 in exon 9, resulting in a frameshift. This mutation was found in the SH3 domain. mutations BTK, 1-BP DEL/3-BP INS, CODON 261 number 24 clinvarAccessions RCV000012118;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621194 text In a patient with severe X-linked agammaglobulinemia ({300755}), {13:de Weers et al. (1994)} identified a C-to-T transition at position 993, resulting in a substitution of tryptophan for arginine-288. This mutation was found in the SH2-like domain where arg288 is highly conserved and crucial for the interaction with the aromatic ring of phosphotyrosine. Therefore, the replacement of arg288 by a nonpolar tryptophan would entirely abrogate the formation of the high-affinity complex with phosphotyrosine. mutations BTK, ARG288TRP number 25 clinvarAccessions RCV000012119;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621195 text In a patient with severe X-linked agammaglobulinemia ({300755}), {2:Bradley et al. (1994)} identified an A-to-G transition at position 1051, resulting in a substitution of glycine for arginine-307. This mutation was found in the SH2-like domain where arg307 is involved in the binding interactions at the base of the phosphotyrosine binding pocket. The change to a neutral glycine residue is highly likely to disrupt the binding potential of this region. This patient has less than 1% B cells and undetectable immunoglobulin levels, indicating that the replacement of this highly conserved arginine residue completely abolishes the functioning of Btk. mutations BTK, ARG307GLY number 26 clinvarAccessions RCV000012120;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621196 text In a patient with X-linked agammaglobulinemia ({300755}), {16:Hagemann et al. (1994)} identified an A-to-C transition at position 1133 in exon 12, resulting in a substitution of serine for tyrosine-334. This mutation was found in the SH2-like domain where tyr334 is most likely responsible for the substrate recognition. mutations BTK, TYR334SER number 27 clinvarAccessions RCV000012121;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 1-bp (G) deletion that occurred in a run of 3 Gs in the last codon (325) of exon 11 and the first nucleotide of intron 11. This mutation was found in the SH2 domain. mutations BTK, 1-BP DEL, IVS11DS, +1G number 28 clinvarAccessions RCV000012122;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In 3 patients with moderate to severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified an A-to-T substitution at nucleotide 1235, which is the second nucleotide of the acceptor splice site of intron 12. The mutation causes a deletion of 12-bp between residues 1235-1247, a frameshift at codon 372, and a stop codon at position 398. This mutation was found in the SH2 domain. mutations BTK, IVS12AS, A-T, -2 number 29 clinvarAccessions RCV000012123;;1 status live name ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III dbSnps rs128621197 text In a patient with X-linked agammaglobulinemia and growth hormone deficiency ({307200}), {8:Conley et al. (1994)} identified a T-to-G transition in exon 13, resulting in a stop codon at position 375 associated with an absence of Btk transcript. This mutation was found in the SH2 domain. mutations BTK, TYR375TER number 30 clinvarAccessions RCV000012124;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In 4 patients with moderate X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified the 16-bp insertion (duplication) at position 1263 of the cDNA, resulting in a frameshift and a premature stop codon in position 404. This mutation was found in the SH2 domain. mutations BTK, 16-BP INS, NT1263 number 31 clinvarAccessions RCV000012125;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621198 text In 2 patients with moderate X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a T-to-C transition at position 1355, resulting in a substitution of proline for leucine-408. This mutation was found in the SH1 domain. mutations BTK, LEU408PRO number 32 clinvarAccessions RCV000012126;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621199 text In a patient with severe X-linked agammaglobulinemia ({300755}), {13:de Weers et al. (1994)} identified a C-to-A transition at position 1407, resulting in a stop codon at position 425 and a truncated protein. This mutation was found in the ATP-binding site. mutations BTK, TYR425TER number 33 clinvarAccessions RCV000012127;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs41310709 text In a patient with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a C-to-A transition at position 1638, resulting in a stop codon at position 502 and a truncated protein. This mutation was found in the SH1 domain. mutations BTK, CYS502TER number 34 clinvarAccessions RCV000012128;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621200 text In a patient with X-linked agammaglobulinemia ({300755}), {16:Hagemann et al. (1994)} identified a T-to-C transition at position 1648 in exon 15, resulting in a substitution of arginine for cysteine-506 in the middle of the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. mutations BTK, CYS506ARG number 35 clinvarAccessions RCV000012129;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621201 text In 2 patients with moderate to severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} and {16:Hagemann et al. (1994)} identified a C-to-T transition at position 1690, resulting in a stop codon at position 520 (in the middle of the kinase domain) and a truncated protein. mutations BTK, ARG520TER number 36 clinvarAccessions RCV000012130;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621202 text In patients with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} and {16:Hagemann et al. (1994)} identified a G-to-A transition at position 1691, resulting in a substitution of glutamine for arginine-520. Arg-520 is a highly conserved residue among all protein kinases. This mutation was found in the SH1 domain. mutations BTK, ARG520GLN number 37 clinvarAccessions RCV000012131;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {16:Hagemann et al. (1994)} identified a 1-bp deletion (A1720) at codon 530 in exon 16, which is in the substrate specific portion of the SH1 domain. This deletion results in a frameshift that generates a stop codon at nucleotide position 1796-1798 and eliminates the C-terminal portion of the catalytic domain. mutations BTK, 1-BP DEL, 1720A number 38 clinvarAccessions RCV000012132;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a 4-bp (GTTT) deletion at codons 527 and 528 in exon 16, resulting in a frameshift. The patient was the mother of a boy who died suddenly of bacterial sepsis at 11 months of age. The absence of germinal follicles in lymph nodes at autopsy examination of this child suggested the diagnosis of XLA despite the lack of family history of immunodeficiency. The mother was shown to be a carrier of XLA. Analysis of X-chromosome inactivation patterns and DNA demonstrated a pattern consistent with one normal allele and one abnormal allele on SSCP analysis of exon 16. This mutation was found in the kinase domain. mutations BTK, 4-BP DEL, CODON 527, GTTT number 39 clinvarAccessions RCV000012133;;1 status live name ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III dbSnps rs128621203 text In a patient with X-linked agammaglobulinemia and growth hormone deficiency ({307200}), {8:Conley et al. (1994)} identified a T-to-C transition in exon 16, resulting in a substitution of proline for leucine-542 in the substrate binding region. The patient had not experienced major infections and responded well to growth hormone replacement. This mutation was found in the kinase domain. mutations BTK, LEU542PRO number 40 clinvarAccessions RCV000012134;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a G-to-T substitution at codon 544, which is the first nucleotide of the donor splice site of intron 16. The mutation preserved a potential splice donor site and the GT sequence was moved 5-prime by 1 basepair. Use of this splice site would result in a frameshift and a premature stop codon. This mutation was found in the kinase domain. mutations BTK, IVS16DS, G-T, +1 number 41 clinvarAccessions RCV000012135;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621204 text In a patient with mild X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} and {16:Hagemann et al. (1994)} identified a C-to-T transition in exon 17, resulting in a substitution of tryptophan for arginine-562. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. mutations BTK, ARG562TRP number 42 clinvarAccessions RCV000012136;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621205 text In a patient with mild X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a T-to-C transition in exon 17, resulting in a substitution of arginine for tyrosine-581. The wildtype tryptophan at this site is conserved in most serine/threonine kinases as well as in most tyrosine kinases. This mutation was found in the kinase domain. mutations BTK, TYR581ARG number 43 clinvarAccessions RCV000012137;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621206 text In 3 patients with moderate X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified an A-to-G transition at position 1898, resulting in a substitution of glycine for glutamic acid-589. This mutation was found in the SH1 domain. mutations BTK, GLU589GLY number 44 clinvarAccessions RCV000012138;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621207 text In a patient with X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a C-to-A transition in exon 17, resulting in a stop codon at position 591 and a truncated protein. This mutation was found in the kinase domain. mutations BTK, TYR591TER number 45 clinvarAccessions RCV000012139;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621208 text In 2 patients with mild X-linked agammaglobulinemia ({300755}), {2:Bradley et al. (1994)} identified a C-to-A transition at position 1952, resulting in a substitution of aspartic acid for alanine-607 near the 3-prime end of the gene. mutations BTK, ALA607ASP number 46 clinvarAccessions RCV000012140;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621209 text In 2 patients with mild X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a G-to-A transition at position 1970, resulting in a substitution of aspartic acid for glycine-613. This mutation was found in the SH1 domain. mutations BTK, GLY613ASP number 47 clinvarAccessions RCV000012141;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128621210 text In a patient with mild X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} and {16:Hagemann et al. (1994)} identified a T-to-A transition in exon 18, resulting in a substitution of lysine for methionine-630. This mutation was found in the kinase domain. Whether this residue is directly involved in catalytic activity or substrate recognition is not clear. mutations BTK, MET630LYS number 48 clinvarAccessions RCV000012142;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128622211 text In a patient with X-linked agammaglobulinemia ({300755}), {2:Bradley et al. (1994)} identified a G-to-T transition at nucleotide 2038, resulting in a stop codon at position 636 and a loss of the 24 terminal amino acids from the protein, including several highly conserved residues. As there are 3 affected boys in this family who have no detectable B-cells or immunoglobulin, it is likely that the last 24 amino acids of this protein are critical for its correct expression and/or function in B-cell development. mutations BTK, GLU636TER number 49 clinvarAccessions RCV000012143;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}), {13:de Weers et al. (1994)} identified a 6-bp (TTTTAG) insertion at position A2041 in the C-terminal region, resulting in a frameshift and a truncated protein. mutations BTK, 6-BP INS, NT2041 number 50 clinvarAccessions RCV000012144;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs128622212 text In a patient with mild X-linked agammaglobulinemia ({300755}), {8:Conley et al. (1994)} identified a T-to-C transition in exon 19, resulting in a substitution of proline for leucine-652. This leucine defines the 3-prime border of the conserved kinase domain in many tyrosine kinases. mutations BTK, LEU652PRO number 51 clinvarAccessions RCV000012145;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with severe X-linked agammaglobulinemia ({300755}), {56:Zhu et al. (1994)} identified a 26-bp insertion (duplication) at position 2019, resulting in a frameshift and a premature stop codon in position 653. This mutation was found in the SH1 domain. mutations BTK, 26-BP INS, NT2019 number 52 clinvarAccessions RCV000012146;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED dbSnps rs104894770 text {11:Curtis et al. (2000)} identified a missense mutation, 1817G-C (arg562 to pro; R562P), in exon 17 of the BTK gene in cousins with XLA ({300755}). The same mutation was present in both mothers (twin sisters) of the cousins, identifying them as carriers. However, the mutation was absent in all other relatives including the grandmother of the cousins (mother of the twin sisters). This suggested that the mutation had originated in the germline of one of the grandparents or in the zygote. mutations BTK, ARG562PRO number 53 clinvarAccessions RCV000012147;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a patient with X-linked agammaglobulinemia ({300755}) who developed classic type I diabetes at the age of 14 years, {28:Martin et al. (2001)} identified a 2-bp deletion (TG) at nucleotides 54-55 in exon 8 of the BTK gene, resulting in a frameshift at codon 214 in the TH domain and a premature stop codon at position 223 in the SH3 domain of the BTK protein. mutations BTK, 2-BP DEL, 54TG number 54 clinvarAccessions RCV000012148;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text In a Korean family with X-linked agammaglobulinemia ({300755}), {20:Jo et al. (2001)} identified a point mutation in intron 1 of the BTK gene, a G-to-A transversion at position +5. mutations BTK, IVS1DS, G-A, +5 number 55 clinvarAccessions RCV000012149;;1 status live name AGAMMAGLOBULINEMIA, X-LINKED text {21:Jo et al. (2003)} identified BTK mutations in 6 patients with presumed XLA ({300755}) from unrelated Korean families. Of the 6 mutations, 4 were novel, including a 6.1-kb deletion including BTK exons 11-18. The large deletion, identified by long-distance PCR, revealed Alu-Alu mediated recombination that extended from an Alu sequence in intron 10 to another Alu sequence in intron 18, spanning a distance of 6.1 kb. mutations BTK, 6.1-KB DEL number 56 clinvarAccessions RCV000012150;;1 prefix * titles alternativeTitles AGAMMAGLOBULINEMIA TYROSINE KINASE; ATK;; B-CELL PROGENITOR KINASE; BPK preferredTitle BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK textSectionList textSection textSectionTitle Description textSectionContent BTK is a key regulator of B-cell development. Mutations in the BTK gene result in X-linked agammaglobulinemia (XLA; {300755}), an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement ({35:Rawlings and Witte, 1994}). textSectionName description textSectionTitle Cloning textSectionContent Using a positional cloning strategy to identify genes within the XLA locus on the X chromosome, followed by screening a cDNA library derived from a Burkitt lymphoma cell line, {46:Vetrie et al. (1993)} isolated BTK, which they called ATK. The ORF of ATK encodes a 659-amino acid polypeptide. Two alternative initiation codons within the same ORF would result in peptide chains of 571 and 497 amino acids, respectively, if used. ATK shares a high degree of similarity with members of the SRC ({190090}) family of protooncogenes that encode protein-tyrosine kinases. Northern blot analysis of RNAs derived from lymphoid lineages demonstrated that the 2.6-kb ATK mRNA was expressed in a B-cell line and in B cells of 2 patients with chronic lymphocytic leukemia, but not in T cells or a T-cell line. {12:Desiderio (1993)} compared the structure of ATK and LTK ({151520}) with SRC. {42:Tsukada et al. (1993)} independently described BTK as a cytoplasmic tyrosine kinase that they termed BPK. BPK was expressed in all cells of the B lineage and in myeloid cells. {42:Tsukada et al. (1993)} concluded that BPK is not a member of the SRC family based on the following differences: (1) the kinase catalytic domain contains the sequence DLAARN, which is similar to ABL ({189980}), FPS ({190030}), and CSK ({124095}), but different from the SRC family (DLRAAN); (2) BPK lacks the consensus myristoylation signal (glycine at position 2 and lysine or arginine at position 7); (3) BPK lacks the equivalent of tyrosine 527 in SRC in the C-terminal domain following the kinase sequences, which is important in regulation of kinase activity; and (4) the N-terminal region of BPK is unusually long. textSectionName cloning textSectionTitle Gene Structure textSectionContent {36:Rohrer et al. (1994)} determined the genomic organization of the BTK gene. BTK contains 19 exons and spans 37 kb. The region 5-prime to the first untranslated exon lacks TATAA or CAAT boxes, but it contains 3 retinoic acid-binding sites. textSectionName geneStructure textSectionTitle Mapping textSectionContent By in situ hybridization, {46:Vetrie et al. (1993)} mapped the BTK gene to chromosome Xq21.3-q22. {31:Oeltjen et al. (1995)} concluded that the 3-prime end of the GLA gene ({300644}) is 9 kb from the 5-prime end of the BTK gene, and they found 2 additional genes in the region immediately 5-prime to BTK. textSectionName mapping textSectionTitle Gene Function textSectionContent {42:Tsukada et al. (1993)} found that BPK mRNA, protein expression, and kinase activity were all reduced or absent in XLA pre-B and B cell lines. Although evidence from the study of XLA indicated that BTK plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remained unknown, primarily because the proteins that it interacts with had not been identified until the work of {6:Cheng et al. (1994)}. They showed that BTK interacted with SRC homology 3 domains of FYN ({137025}), LYN ({165120}), and HCK ({142370}). All of these are protein-tyrosine kinases that are activated upon stimulation of B- and T-cell receptors. These interactions were mediated by two 10-amino acid motifs in BTK. An analogous site with the same specificity was also identified in ITK ({186973}), the T-cell-specific homolog of BTK. The findings of {6:Cheng et al. (1994)} extended the range of interactions mediated by SRC homology 3 domains and provided an indication of a link between BTK and previously established signaling pathways in B lymphocytes. {43:Uckun et al. (1996)} noted that a number of human diseases including immune deficiencies apparently stem from inherited or acquired deficiencies of checkpoints that regulate the rate of apoptosis in lymphoid cells. {43:Uckun et al. (1996)} reported that DT-40 lymphoma B cells rendered BTK deficient through targeted disruption of the BTK gene did not undergo radiation-induced apoptosis. They further demonstrated that the tyrosine kinase domain of BTK was necessary for triggering radiation-induced apoptosis. {30:Ng et al. (2004)} tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients with XLA and found that XLA B cells were selected to express a unique antibody repertoire using distinct VH and D genes favoring hydrophobic reading frames normally counterselected in healthy donor B cells. Patient B cells appeared to undergo extensive secondary recombination on both IgK (see {147200}) and IgL (see {147220}) loci and had a slightly increased proportion of cells expressing antinuclear antibodies. {30:Ng et al. (2004)} concluded that almost half of the antibodies expressed by XLA B cells are polyreactive and that BTK is essential for removal of autoreactive B cells. {18:Hantschel et al. (2007)} identified the BTK tyrosine kinase and TEC kinase ({600583}) as major binders of the tyrosine kinase inhibitor dasatinib, which is used for treatment of BCR/ABL (see {151410})-positive CML ({608232}). Dasatinib did not bind ITK. In a CML cell line, they determined that a thr474-to-ile (T474I) substitution in the BTK gene conferred resistance to dasatinib. They suggested that, like the structurally homologous thr315 residue in the ABL gene (see {189980.0001}), the BTK thr474 residue is the gatekeeper residue critical for dasatinib binding. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The findings suggested that dasatinib may have immunosuppressive side effects. Using ELISA, microarray analysis, RT-PCR, and flow cytometry, {19:Hasan et al. (2007)} demonstrated that Btk -/- mouse B cells responded more efficiently to CpG-DNA stimulation by producing higher levels of proinflammatory cytokines and Il27 ({608273}), but lower levels of the inhibitory cytokine Il10 ({124092}). Tlr9 ({605474}) protein and mRNA expression was enhanced in Btk -/- cells, especially after Tlr9 stimulation. Whereas Btk -/- and wildtype transitional stage-1 (T1) B cells failed to proliferate and died after CpG stimulation, T2 cells, expressing higher levels of Tlr9, proliferated and matured. {19:Hasan et al. (2007)} concluded that BTK regulates both TLR9 activation and expression in B lymphocytes and is necessary for inhibitory cytokine expression. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent {49:Vihinen et al. (1994)} used a 3-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, to interpret the structural basis for disease in 8 independent point mutations in patients with XLA. Because arg525 of BTK had been thought to substitute functionally for a critical lysine residue in protein-serine kinases, they studied the arg525-to-gln mutation and found that it abrogated the tyrosine kinase activity of BTK. All of the 8 mutations, including lys430-to-glu ({300300.0002}), were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues. {26:Mao et al. (2001)} determined the x-ray crystal structure of the BTK kinase domain in its unphosphorylated state to 2.1-angstrom resolution. The structure suggested that the trans-phosphorylation of tyr551 can lead to BTK activation by triggering an exchange of hydrogen-bonded pairs from glu445/arg544 to glu445/lys430 and subsequent relocation of helix alpha-C of the N-terminal lobe. The model also indicated that mutations in the C-terminal lobe of the kinase domain, such as R562W ({300300.0042}), are directly or indirectly involved in peptide substrate binding. Other disease-associated mutations in this domain (e.g., E589G; {300300.0044}) alter interactions with neighboring residues. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent Using probes derived for the Southern analysis of DNA from 33 unrelated families and 150 normal X chromosomes, {46:Vetrie et al. (1993)} detected restriction pattern abnormalities in 8 families. Five of them had deletions that were shown to be entirely intragenic to BTK, confirming involvement of BTK in XLA. Two single-base missense mutations were identified in XLA patients. The failure of pre-B cells in the bone marrow of XLA males to develop into mature, circulating B cells could be the result of the product of the mutant ATK gene failing to fulfill its role in B-cell signaling. {46:Vetrie et al. (1993)} noted that inactivation of the mouse Lck gene ({153390}), another member of the SRC family of tyrosine kinases, results in a thymocyte differentiation defect. {51:Vorechovsky et al. (1993)} pointed out that common variable immunodeficiency (CVID) is sometimes clinically and immunologically indistinguishable from XLA if it starts early in childhood and occurs sporadically in males with a decreased number of B cells. Using a cDNA clone that represented the full-length ATK cDNA, {51:Vorechovsky et al. (1993)} did Southern blot analysis of 39 Swedish male patients diagnosed with CVID or possible CVID. One man in his late 40s, who had had recurrent respiratory infections from infancy, lacked immunoglobulins of all isotypes, and had less than 1% B cells among peripheral blood mononuclear cells, had an abnormality of the ATK gene. The abnormality was missing in his mother but had been inherited by both of his daughters. {51:Vorechovsky et al. (1993)} failed to find the arg28-to-cys mutation, which is found in xid in mice (see ANIMAL MODEL), in 13 unrelated patients with XLA and 2 patients with the syndrome of XLA and growth hormone deficiency ({307200}). They pointed to the milder phenotype of the xid mouse compared to XLA cases and suggested that if this particular mutation occurs in the human BTK gene, it might result in a milder phenotype with normal or only moderately reduced B cells and more selective immunoglobulin deficiency in boys, which may or may not increase susceptibility to infections. {33:Parolini et al. (1993)} identified a family in which a healthy father transmitted the XLA defect to 2 of his daughters, indicating gonadal or somatic mosaicism. To assess the frequency of this phenomenon, {9:Conley et al. (1998)} evaluated 11 sisters of 7 women who were carriers of XLA and whose mutation occurred on the paternal haplotype. None of the 11 sisters were carriers of the mutations seen in their nephews. {15:Duriez et al. (1994)} found an exon-skipping mutation in the BTK gene which appeared to account for the syndrome of X-linked agammaglobulinemia and isolated growth hormone deficiency in a sporadic case (see {300300.0004}). {32:Ohta et al. (1994)} reported the DNA sequence of the 18 coding exons of BTK and their flanking regions. Correlations were made between the nature of mutations and the organization of the BTK gene. They found several examples of the same mutation occurring in unrelated patients, and one of these mutations occurred at the same codon that is substituted in the xid mouse. However, in xid, the mutation occurs at the first position in the conserved arginine codon, C214-to-T, and results in an arg28-to-cys amino acid change, whereas in human cases it occurs in the second nucleotide, G215-to-A, and results in an arg28-to-his amino acid change ({300300.0005}). The observations suggested that a limited number of deleterious changes in BTK produce clinically recognizable XLA. XLA patients have been classified in 2 general groups: those presenting at an early age with particularly severe infections and those with less severe disease in which production of immunoglobulin is sustained at low-to-normal levels well into the first decade of life. In the latter cases, an oncogenetic change may occur in which the defective tyrosine kinase no longer can sustain the B-cell population, and a progressive reduction in immunoglobulin production occurs. {32:Ohta et al. (1994)} described the arg525-to-gln mutation ({300300.0001}) in patients whose disorder might have been classified as common variable immunodeficiency disease. These patients had low levels of circulating B cells at an early age with mildly decreased IgM and variable IgG levels, although all were IgA deficient. {25:Kornfeld et al. (1995)} described the case of a 16-year-old boy who had recurrent upper respiratory tract infections at 13 months of age and was diagnosed as having transient hypogammaglobulinemia of infancy on the basis of low immunoglobulin levels, normal diphtheria and tetanus antibody responses, normal anterior and posterior cervical nodes, normal tonsillar tissue, and normal numbers of B cells in the blood. IgA levels returned to normal at 15 months of age and remained within normal limits over the next 12 months, and IgG and IgM levels remained relatively unchanged. At age 10, he began receiving intravenous gammaglobulin, which resulted in cessation of infections. The clinical picture was thought to be that of common variable immunodeficiency disease. However, gene studies revealed the deletion of exon 16 of the BTK gene resulting from a splice junction defect. The patient represents an example of the extreme variation that can occur in the XLA phenotype. {17:Hagemann et al. (1995)} described 6 mutations in the BTK gene as the cause of XLA; 5 were novel. The mutations included 2 nonsense and 2 missense mutations, a single base deletion at an intron acceptor splice site, and a 16-bp insertion. {24:Kobayashi et al. (1996)} reported abnormalities in the BTK gene in 12 unrelated Japanese families with X-linked agammaglobulinemia. Gene rearrangement in the kinase domain was found in 2 patients by Southern blotting. Seven point mutations, 2 small deletions, and 1 small insertion were detected by SSCP analysis and sequencing. Phenotypic heterogeneity was observed in affected family members with the same mutation. The authors concluded that analyzing BTK gene alterations with SSCP is valuable for the diagnosis of XLA patients and for carrier detection; however, the correlation between gene abnormalities and clinical features remains unclear. Among 26 unrelated patients with XLA, {50:Vorechovsky et al. (1997)} found 24 different mutations of the BTK gene. Most resulted in the premature termination of translation. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5-prime end of the gene and missense mutations in its 3-prime part, corresponding to the catalytic domain of the enzyme. {9:Conley et al. (1998)} analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in the BTK gene were identified in 38 of 40 families with more than 1 affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in BTK were identified in 43 of 46 patients with presumed sporadic XLA. Two of the 3 remaining patients had defects in other genes required for normal B cell development, namely the mu heavy chain gene (IGHM1; {147020}), as reported by {55:Yel et al. (1996)} or the lambda-5/14.1 surrogate light chain gene (IGLL1; {146770}), as reported by {29:Minegishi et al. (1998)}. Both of these patients were compound heterozygotes and there were no clinical features that would distinguish them from patients with typical XLA. An Epstein-Barr virus-transformed cell line from a third patient had normal BTK cDNA by SSCP, normal BTK message by Northern blot, and normal BTK protein by Western blot. Therefore, it is unlikely that this patient had XLA. Ten mutations were found in more than one family; 1 of these occurred in 3 families. Of the 83 unique mutations included in the study of {9:Conley et al. (1998)}, 43 had been described previously by their laboratory, 5 had been reported by other groups, and 35 had not been previously described. In a study of 12 Korean patients with X-linked agammaglobulinemia, {20:Jo et al. (2001)} identified 7 mutations in the BTK gene, including a point mutation in intron 1 ({300300.0055}). Luciferase analysis showed reduced transcriptional activity in the intron-1 mutant compared with the wildtype. EMSA and functional analysis indicated that a nuclear protein had the ability to bind to the intron-1 mutant oligonucleotides. {20:Jo et al. (2001)} proposed that several regulatory elements mediate the transcriptional regulation of BTK and that the first intron is important in BTK promoter activity. {38:Sakamoto et al. (2001)} suggested maternal germinal mosaicism to explain the finding of 2 sibs with XLA who had a single base deletion (563C) in exon 6 of the BTK gene and whose mother had no evidence of the mutation. Cytoplasmic expression of BTK protein in monocytes was not detected in either patient; normal cytoplasmic expression of BTK protein was found in monocytes of the mother. {28:Martin et al. (2001)} identified a 2-bp deletion in the BTK gene ({300300.0054}) in a patient with X-linked agammaglobulinemia who developed classic type I diabetes (see {222100}) at the age of 14 years. Autoantibodies associated with type I diabetes were undetectable, a result consistent with the diagnosis of X-linked agammaglobulinemia. The patient's HLA type was the one that is associated with the highest genetic risk of type I diabetes. The data implied that autoantibodies are not required for either the initiation or the progression of type I diabetes. {28:Martin et al. (2001)} concluded that type I diabetes can develop in the absence of both autoantibodies and B cells. This aspect of its pathogenesis places type I diabetes in marked contrast to spontaneous autoimmune diabetes in NOD mice, which has been claimed to be B cell-dependent. The findings suggested that immunotherapy directed specifically toward B cells or autoantibodies may not be effective in preventing the destruction of beta cells. {53:Wattanasirichaigoon et al. (2006)} reported 7 different mutations in the BTK gene among 7 patients with XLA; 4 of the mutations were novel. Six patients were Thai, and 1 patient was Burmese. About 60% of DCLRE1C ({605988}) and IGHM ({147020}) gene defects involve gross deletions, compared with about 6% of BTK gene defects. {45:Van Zelm et al. (2008)} compared gross deletion breakpoints involving DCLRE1C, IGHM, and BTK to identify mechanisms underlying these differences in gross deletion frequencies. Their analysis suggested that gross deletions involve transposable elements or large homologous regions rather than recombination motifs. {45:Van Zelm et al. (2008)} hypothesized that the transposable element content of a gene is related to its gross deletion frequency. BTK Mutation Database {47:Vihinen et al. (1996)} described a database of BTK mutations (BTKbase) listing entries from 189 unrelated families showing 148 unique molecular events. Information was included regarding the phenotype. Mutations in all 5 domains of the BTK had been observed to cause XLA, the most common class of changes being missense mutations. The mutations appeared almost uniformly throughout the molecule and frequently affected CpG sites forming arginine residues. {48:Vihinen et al. (1999)} reported that BTKbase listed 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms had been found. Most mutations led to truncation of the enzyme, and about one-third of point mutations affected CpG sites. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Presumably the X-linked B-lymphocyte defect of mice, studied by {27:Marshall-Clarke et al. (1979)}, is homologous. This defect is characteristic of the CBA-N strain of mice ({39:Scher et al., 1975}). Defective mice lack the subpopulation of B lymphocytes responsive to certain T-independent antigens of which trinitrophenylated (TNP)-Ficoll is the prototype. Their responses to T-dependent antigens may also be impaired and they are unable to respond to the hapten phosphorylcholine (PC). They lack those B cells that form colonies when cultured in vitro. {7:Cohen et al. (1985)} isolated a cDNA probe recognizing a family of genes, called XLR, on the mouse X chromosome, at least some members of which are closely linked to the X-linked immunodeficiency (xid) trait. Linkage studies involving 1,114 progeny backcross revealed colocalization of the xid mutation in mice with the Btk gene ({41:Thomas et al., 1993}). The xid mutation was associated in mice with a missense mutation that altered the highly conserved arginine near the N terminus of the Btk protein. Because this region of the protein lies outside any obvious kinase domain, the xid mutation may define another aspect of tyrosine kinase. {34:Rawlings et al. (1993)} likewise mapped the xid and the Btk gene to the same region and demonstrated the same missense mutation, an arg28-to-cys change. {14:Drabek et al. (1997)} generated transgenic mice in which expression of the human BTK gene was driven by the murine class II major histocompatibility complex Ea gene locus control region, which provides gene expression from the pre-B cell stage onwards. When these transgenic mice were mated onto a Btk(-) background, correction of the xid B cell defects was observed: B cells differentiated to mature low IgM/high IgD stages, peritoneal CD5(+) B cells were present, and serum immunoglobulin levels and in vivo responses to antigens were in the normal ranges. A comparable rescue by transgenic Btk expression was also observed in heterozygous Btk +/- female mice in those B-lineage cells that were Btk-deficient as a result of X-chromosome inactivation. {23:Kawakami et al. (2006)} found that dendritic cells of Btk-null mice exhibited a more mature phenotype and a stronger in vitro and in vivo T cell-stimulatory ability than wildtype cells. Increased IgE responses were induced by adoptive transfer of Btk-null dendritic cells into wildtype mice. Consistent with the stronger T cell-stimulatory ability of Btk-null dendritic cells, Btk-null mice exhibited enhanced inflammation in T helper cell 2-driven asthma and T helper cell 1-driven contact sensitivity experiments. The negative regulatory functions of Btk in dendritic cells appeared to be mediated mainly through autocrine secretion of IL10 ({124092}) and subsequent activation of Stat3 ({102582}). Using Tec ({600583}) -/- Btk -/- double-knockout mice, {40:Shinohara et al. (2008)} showed that these tyrosine kinases were crucial in Rankl (TNFSF11; {602642})-induced osteoclastogenesis. In response to Rankl stimulation, Btk and Tec formed a signaling complex required for osteoclastogenesis with adaptor molecules such as Blnk ({604515}), which also recruited Syk ({600085}), linking Rank (TNFRSF11A; {603499}) and ITAM (see {608740}) signals to phosphorylate Plc-gamma (see {172420}). Tec kinase inhibition reduced osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. {40:Shinohara et al. (2008)} concluded that their studies provided a link between immunodeficiency and abnormal bone homeostasis owing to defects in signaling molecules shared by B cells and osteoclasts. textSectionName animalModel geneMapExists true editHistory terry : 03/28/2013 terry : 3/28/2013 terry : 10/3/2012 wwang : 2/17/2010 wwang : 9/23/2009 alopez : 6/2/2009 alopez : 5/6/2009 mgross : 2/2/2009 mgross : 12/19/2008 mgross : 12/18/2008 mgross : 11/25/2008 terry : 11/21/2008 wwang : 10/23/2008 ckniffin : 10/13/2008 mgross : 5/2/2008 mgross : 2/21/2008 wwang : 4/2/2007 carol : 3/28/2007 ckniffin : 3/21/2007 terry : 10/11/2006 mgross : 5/3/2006 terry : 4/11/2006 wwang : 4/4/2006 terry : 3/27/2006 ckniffin : 10/28/2004 carol : 3/17/2004 alopez : 1/15/2004 terry : 1/15/2004 carol : 6/11/2003 mgross : 1/25/2002 mgross : 1/9/2002 mcapotos : 11/14/2001 carol : 11/9/2001 mcapotos : 11/7/2001 terry : 10/30/2001 carol : 10/19/2001 carol : 10/19/2001 carol : 9/27/2001 cwells : 3/20/2001 terry : 3/13/2001 mcapotos : 1/22/2001 alopez : 2/25/2000 terry : 2/23/2000 alopez : 11/15/1999 mgross : 10/8/1999 terry : 9/23/1999 mgross : 6/3/1999 mgross : 5/26/1999 terry : 5/14/1999 dkim : 12/9/1998 alopez : 10/14/1998 carol : 8/18/1998 terry : 8/17/1998 dholmes : 7/9/1998 carol : 7/2/1998 terry : 6/4/1998 alopez : 6/3/1998 terry : 5/15/1998 mark : 12/22/1997 mark : 11/21/1997 alopez : 7/30/1997 terry : 7/24/1997 mark : 7/8/1997 carol : 6/23/1997 jenny : 6/23/1997 mark : 6/18/1997 mark : 2/12/1997 terry : 2/6/1997 terry : 1/7/1997 jenny : 12/9/1996 terry : 11/18/1996 mark : 11/12/1996 mark : 11/11/1996 mark : 8/29/1996 carol : 7/6/1996 joanna : 3/22/1996 mark : 3/13/1996 terry : 3/13/1996 mark : 3/13/1996 mark : 3/13/1996 terry : 3/12/1996 mark : 3/6/1996 terry : 3/4/1996 mark : 10/24/1995 terry : 8/10/1995 davew : 8/25/1994 jason : 7/15/1994 mimadm : 5/12/1994 warfield : 3/21/1994 dateCreated Wed, 04 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/4/1986 epochUpdated 1364454000 dateUpdated Thu, 28 Mar 2013 03:00:00 EDT referenceList reference articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=7365241 publisherName HighWire Press title Mapping of the X-linked immune deficiency mutation (xid) of CBA/N mice. mimNumber 300300 referenceNumber 1 publisherAbbreviation HighWire pubmedID 7365241 source J. Immun. 124: 1875-1877, 1980. authors Berning, A. K., Eicher, E. M., Paul, W. E., Scher, I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8162056 publisherName HighWire Press title Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. mimNumber 300300 referenceNumber 2 publisherAbbreviation HighWire pubmedID 8162056 source Hum. Molec. Genet. 3: 79-83, 1994. authors Bradley, L. A. D., Sweatman, A. K., Lovering, R. C., Jones, A. M., Morgan, G., Levinsky, R. 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(Abstract) mimNumber 300300 referenceNumber 12 publisherAbbreviation NPG pubmedID 7678697 source Nature 361: 202, 1993. authors Desiderio, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8162018 publisherName HighWire Press title Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. mimNumber 300300 referenceNumber 13 publisherAbbreviation HighWire pubmedID 8162018 source Hum. Molec. Genet. 3: 161-166, 1994. authors de Weers, M., Mensink, R. G. J., Kraakman, M. E. M., Schuurman, R. K. B., Hendriks, R. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9012832 publisherName HighWire Press title Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region. mimNumber 300300 referenceNumber 14 publisherAbbreviation HighWire pubmedID 9012832 source Proc. Nat. Acad. Sci. 94: 610-615, 1997. authors Drabek, D., Raguz, S., De Wit, T. P. M., Dingjan, G. M., Savelkoul, H. F. J., Grosveld, F., Hendriks, R. W. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0014-5793(94)00457-9 publisherName Elsevier Science title An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. mimNumber 300300 referenceNumber 15 publisherAbbreviation ES pubmedID 8013627 source FEBS Lett. 346: 165-170, 1994. authors Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7880320 publisherName HighWire Press title Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 16 publisherAbbreviation HighWire pubmedID 7880320 source Hum. Molec. Genet. 3: 1743-1749, 1994. authors Hagemann, T. L., Chen, Y., Rosen, F. S., Kwan, S.-P. pubmedImages false publisherUrl http://highwire.stanford.edu title Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 17 pubmedID 7627183 source Hum. Mutat. 5: 296-302, 1995. authors Hagemann, T. L., Rosen, F. S., Kwan, S.-P. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17684099 publisherName HighWire Press title The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. mimNumber 300300 referenceNumber 18 publisherAbbreviation HighWire pubmedID 17684099 source Proc. Nat. Acad. Sci. 104: 13283-13288, 2007. authors Hantschel, O., Rix, U., Schmidt, U., Burckstummer, T., Kneidinger, M., Schutze, G., Colinge, J., Bennett, K. L., Ellmeier, W., Valent, P., Superti-Furga, G. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1111/j.1365-2567.2007.02693.x publisherName Blackwell Publishing title Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice. mimNumber 300300 referenceNumber 19 publisherAbbreviation Blackwell pubmedID 17725607 source Immunology 123: 239-249, 2007. authors Hasan, M., Lopez-Herrera, G., Blomberg, K. E. M., Lindvall, J. M., Berglof, A., Smith, C. I. E., Vargas, L. pubmedImages true publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11564824 publisherName HighWire Press title Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase gene from seven Korean X-linked agammaglobulinemia families. mimNumber 300300 referenceNumber 20 publisherAbbreviation HighWire pubmedID 11564824 source J. Immun. 167: 4038-4045, 2001. authors Jo, E.-K., Kanegane, H., Nonoyama, S., Tsukada, S., Lee, J.-H., Lim, K., Shong, M., Song, C.-H., Kim, H.-J., Park, J.-K., Miyawaki, T. pubmedImages false publisherUrl http://highwire.stanford.edu title Identification of mutations in the Bruton's tyrosine kinase gene, including a novel genomic rearrangements (sic) resulting in large deletion, in Korean X-linked agammaglobulinemia patients. mimNumber 300300 referenceNumber 21 pubmedID 12768435 source J. Hum. Genet. 48: 322-326, 2003. authors Jo, E.-K., Wang, Y., Kanegane, H., Futatani, T., Song, C.-H., Park, J.-K., Kim, J. S., Kim, D. S., Ahn, K.-M., Lee, S.-I., Park, H. J., Hahn, Y. S., Lee, J.-H., Miyawaki, T. pubmedImages false title X linked agammaglobulinaemia with a 'leaky' phenotype. mimNumber 300300 referenceNumber 22 pubmedID 8758136 source Arch. Dis. Child. 74: 548-549, 1996. authors Jones, A., Bradley, L., Alterman, L., Tarlow, M., Thompson, R., Kinnon, C., Morgan, G. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16371463 publisherName HighWire Press title Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3. mimNumber 300300 referenceNumber 23 publisherAbbreviation HighWire pubmedID 16371463 source Proc. Nat. Acad. Sci. 103: 153-158, 2006. authors Kawakami, Y., Inagaki, N., Salek-Ardakani, S., Kitaura, J., Tanaka, H., Nagao, K., Kawakami, Y., Xiao, W., Nagai, H., Croft, M., Kawakami, T. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/6097004/60970424.htm publisherName Springer title Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan. mimNumber 300300 referenceNumber 24 publisherAbbreviation Springer pubmedID 8834236 source Hum. Genet. 97: 424-430, 1996. authors Kobayashi, S., Iwata, T., Saito, M., Iwasaki, R., Matsumoto, H., Naritaka, S., Kono, Y., Hayashi, Y. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(95)70138-9 publisherName Elsevier Science title X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. mimNumber 300300 referenceNumber 25 publisherAbbreviation ES pubmedID 7722175 source J. Allergy Clin. Immun. 95: 915-917, 1995. authors Kornfeld, S. J., Kratz, J., Haire, R. N., Litman, G. W., Good, R. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11527964 publisherName HighWire Press title Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 26 publisherAbbreviation HighWire pubmedID 11527964 source J. Biol. Chem. 276: 41435-41443, 2001. authors Mao, C., Zhou, M., Uckun, F. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/eji.1830091014 publisherName John Wiley & Sons, Inc. title Deficient production of anti-red cell autoantibodies by mice with an X-linked B-lymphocyte defect. mimNumber 300300 referenceNumber 27 publisherAbbreviation Wiley pubmedID 316393 source Europ. J. Immun. 9: 820-823, 1979. authors Marshall-Clarke, S., Cooke, A., Hutchings, P. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa010465?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Development of type 1 diabetes despite severe hereditary B-cell deficiency. mimNumber 300300 referenceNumber 28 publisherAbbreviation ATYPON pubmedID 11586956 source New Eng. J. Med. 345: 1036-1040, 2001. authors Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G., Roep, B. O. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.jem.org/cgi/pmidlookup?view=long&pmid=9419212 publisherName HighWire Press title Mutations in the human lambda-5/14.1 gene result in B cell deficiency and agammaglobulinemia. mimNumber 300300 referenceNumber 29 publisherAbbreviation HighWire pubmedID 9419212 source J. Exp. Med. 187: 71-77, 1998. authors Minegishi, Y., Coustan-Smith, E., Wang, Y.-H., Cooper, M. D., Campana, D., Conley, M. E. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.jem.org/cgi/pmidlookup?view=long&pmid=15466623 publisherName HighWire Press title Bruton's tyrosine kinase is essential for human B cell tolerance. mimNumber 300300 referenceNumber 30 publisherAbbreviation HighWire pubmedID 15466623 source J. Exp. Med. 200: 927-934, 2004. authors Ng, Y.-S., Wardemann, H., Chelnis, J., Cunningham-Rundles, C., Meffre, E. pubmedImages true publisherUrl http://highwire.stanford.edu title Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci. mimNumber 300300 referenceNumber 31 pubmedID 7626884 source Mammalian Genome 6: 334-338, 1995. authors Oeltjen, J. C., Liu, X., Lu, J., Allen, R. C., Muzny, D., Belmont, J. W., Gibbs, R. A. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8090769 publisherName HighWire Press title Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. mimNumber 300300 referenceNumber 32 publisherAbbreviation HighWire pubmedID 8090769 source Proc. Nat. Acad. Sci. 91: 9062-9066, 1994. authors Ohta, Y., Haire, R. N., Litman, R. T., Fu, S. M., Nelson, R. P., Kratz, J., Kornfeld, S. J., de la Morena, M., Good, R. A., Litman, G. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71066-9 publisherName Elsevier Science title Linkage analysis and physical mapping near the gene for X-linked agammaglobulinemia at Xq22. mimNumber 300300 referenceNumber 33 publisherAbbreviation ES pubmedID 8449500 source Genomics 15: 342-349, 1993. authors Parolini, O., Hejtmancik, J. F., Allen, R. C., Belmont, J. W., Lassiter, G. L., Henry, M. J., Barker, D. F., Conley, M. E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8332901 publisherName HighWire Press title Mutation of unique region of Bruton's tyrosine kinase in immunodeficient xid mice. mimNumber 300300 referenceNumber 34 publisherAbbreviation HighWire pubmedID 8332901 source Science 261: 358-361, 1993. authors Rawlings, D. J., Saffran, D. C., Tsukada, S., Largaespada, D. A., Grimaldi, J. C., Cohen, L., Mohr, R. N., Bazan, J. F., Howard, M., Copeland, N. G., Jenkins, N. A., Witte, O. N. pubmedImages false publisherUrl http://highwire.stanford.edu title Bruton's tyrosine kinase is a key regulator in B-cell development. mimNumber 300300 referenceNumber 35 pubmedID 8070812 source Immun. Rev. 138: 105-119, 1994. authors Rawlings, D. J., Witte, O. N. pubmedImages false title The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 36 pubmedID 7927535 source Immunogenetics 40: 319-324, 1994. Note: Erratum: Immunogenetics 42: 76 only, 1995. authors Rohrer, J., Parolini, O., Belmont, J. W., Conley, M. E. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199405263302104?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title A point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 37 publisherAbbreviation ATYPON pubmedID 8164701 source New Eng. J. Med. 330: 1488-1491, 1994. authors Saffran, D. C., Parolini, O., Fitch-Hilgenberg, M. E., Rawlings, D. J., Afar, D. E. H., Witte, O. N., Conley, M. E. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1002/1096-8628(2001)9999:9999<::AID-AJMG1159>3.0.CO;2-M publisherName John Wiley & Sons, Inc. title Maternal germinal mosaicism of X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 38 publisherAbbreviation Wiley pubmedID 11241495 source Am. J. Med. Genet. 99: 234-237, 2001. authors Sakamoto, M., Kanegane, H., Fujii, H., Tsukada, S., Miyawaki, T., Shinomiya, N. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title X-linked B-lymphocyte immune defect in CBA-N mice. II. Studies of the mechanisms underlying the immune defect. mimNumber 300300 referenceNumber 39 pubmedID 1080788 source J. Exp. Med. 142: 637-650, 1975. authors Scher, I., Steinberg, A. D., Berning, A. K., Paul, W. E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(08)00058-5 publisherName Elsevier Science title Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. mimNumber 300300 referenceNumber 40 publisherAbbreviation ES pubmedID 18329366 source Cell 132: 794-806, 2008. authors Shinohara, M., Koga, T., Okamoto, K., Sakaguchi, S., Arai, K., Yasuda, H., Takai, T., Kodama, T., Morio, T., Geha, R. S., Kitamura, D., Kurosaki, T., Ellmeier, W., Takayanagi, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8332900 publisherName HighWire Press title Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. mimNumber 300300 referenceNumber 41 publisherAbbreviation HighWire pubmedID 8332900 source Science 261: 355-358, 1993. authors Thomas, J. D., Sideras, P., Smith, C. I. E., Vorechovsky, I., Chapman, V., Paul, W. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(93)90667-F publisherName Elsevier Science title Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 42 publisherAbbreviation ES pubmedID 8425221 source Cell 72: 279-290, 1993. authors Tsukada, S., Saffran, D. C., Rawlings, D. J., Parolini, O., Allen, R. C., Klisak, I., Sparkes, R. S., Kubagawa, H., Mohandas, T., Quan, S., Belmont, J. W., Cooper, M. D., Conley, M. E., Witte, O. N. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8688094 publisherName HighWire Press title BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells. mimNumber 300300 referenceNumber 43 publisherAbbreviation HighWire pubmedID 8688094 source Science 273: 1096-1099, 1996. authors Uckun, F. M., Waddick, K. G., Mahajan, S., Jun, X., Takata, M., Bolen, J., Kurosaki, T. pubmedImages false publisherUrl http://highwire.stanford.edu title Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia. mimNumber 300300 referenceNumber 44 pubmedID 3722839 source J. Infect. 12: 235-239, 1986. authors van der Meer, J. W. M., Mouton, R. P., Daha, M. R., Schuurman, R. K. B. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(08)00090-6 publisherName Elsevier Science title Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. mimNumber 300300 referenceNumber 45 publisherAbbreviation ES pubmedID 18252213 source Am. J. Hum. Genet. 82: 320-332, 2008. authors van Zelm, M. C., Geertsema, C., Nieuwenhuis, N., de Ridder, D., Conley, M. E., Schiff, C., Tezcan, I., Bernatowska, E., Hartwig, N. G., Sanders, E. A. M., Litzman, J., Kondratenko, I., van Dongen, J. J. M., van der Burg, M. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/361226a0 publisherName Nature Publishing Group title The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. mimNumber 300300 referenceNumber 46 publisherAbbreviation NPG pubmedID 8380905 source Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362 only, 1993. authors Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C. I. E., Bentley, D. R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8594569 publisherName HighWire Press title BTKbase, mutation database for X-linked agammaglobulinemia (XLA). mimNumber 300300 referenceNumber 47 publisherAbbreviation HighWire pubmedID 8594569 source Nucleic Acids Res. 24: 160-165, 1996. authors Vihinen, M., Iwata, T., Kinnon, C., Kwan, S.-P., Ochs, H. D., Vorechovsky, I., Smith, C. I. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:4<280::AID-HUMU3>3.0.CO;2-L publisherName John Wiley & Sons, Inc. title Mutations of the human BTK gene coding for Bruton tyrosine kinase in X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 48 publisherAbbreviation Wiley pubmedID 10220140 source Hum. Mutat. 13: 280-285, 1999. authors Vihinen, M., Kwan, S.-P., Lester, T., Ochs, H. D., Resnick, I., Valiaho, J., Conley, M. E., Smith, C. I. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7809124 publisherName HighWire Press title Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease. mimNumber 300300 referenceNumber 49 publisherAbbreviation HighWire pubmedID 7809124 source Proc. Nat. Acad. Sci. 91: 12803-12807, 1994. authors Vihinen, M., Vetrie, D., Maniar, H. S., Ochs, H. D., Zhu, Q., Vorechovsky, I., Webster, A. D. B., Notarangelo, L. D., Nilsson, L., Sowadski, J. M., Smith, C. I. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:5<418::AID-HUMU7>3.0.CO;2-%23 publisherName John Wiley & Sons, Inc. title Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia. mimNumber 300300 referenceNumber 50 publisherAbbreviation Wiley pubmedID 9143921 source Hum. Mutat. 9: 418-425, 1997. authors Vorechovsky, I., Luo, L., Hertz, J. M., Froland, S. S., Klemola, T., Fiorini, M., Quinti, I., Paganelli, R., Ozsahin, H., Hammarstrom, L., Webster, A. D. B., Smith, C. I. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(93)91676-D publisherName Elsevier Science title Absence of xid mutation in X-linked agammaglobulinaemia. (Letter) mimNumber 300300 referenceNumber 51 publisherAbbreviation ES pubmedID 8102684 source Lancet 342: 552, 1993. authors Vorechovsky, I., Zhou, J.-N., Hammarstrom, L., Smith, C. I. E., Thomas, J. D., Paul, W. E., Notarangelo, L. D., Bernatowska-Matuszkiewicz, E. pubmedImages false publisherUrl http://www.elsevier.com/ source Lancet 341: 1153, 1993. Note: Erratum: Lancet 361: 1394 only, 2003. mimNumber 300300 authors Vorechovsky, I., Zhou, J.-N., Vetrie, D., Bentley, D., Bjorkander, J., Hammarstrom, L., Smith, C. I. E. title Molecular diagnosis of X-linked agammaglobulinaemia. (Letter) referenceNumber 52 title Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations. mimNumber 300300 referenceNumber 53 pubmedID 16951917 source J. Hum. Genet. 51: 1006-1014, 2006. authors Wattanasirichaigoon, D., Benjaponpitak, S., Techasaensiri, C., Kamchaisatian, W., Vichyanond, P., Janwityanujit, S., Choubtum, L., Sirinavin, S. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(01)80772-1 publisherName Elsevier Science title A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. mimNumber 300300 referenceNumber 54 publisherAbbreviation ES pubmedID 11445810 source J. Pediat. 139: 148-151, 2001. authors Wood, P. M. D., Mayne, A., Joyce, H., Smith, C. I. E., Granoff, D. M., Kumararatne, D. S. pubmedImages false publisherUrl http://www.elsevier.com/ title Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. mimNumber 300300 referenceNumber 55 pubmedID 8890099 source New Eng. J. Med. 335: 1486-1493, 1996. authors Yel, L., Minegishi, Y., Coustan-Smith, E., Buckley, R. H., Trubel, H., Pachman, L. M., Kitchingman, G. R., Campana, D., Rohrer, J., Conley, M. E. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7849721 publisherName HighWire Press title Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families. mimNumber 300300 referenceNumber 56 publisherAbbreviation HighWire pubmedID 7849721 source Hum. Molec. Genet. 3: 1899-1900, 1994. authors Zhu, Q., Zhang, M., Winkelstein, J., Chen, S.-H., Ochs, H. D. pubmedImages false publisherUrl http://highwire.stanford.edu seeAlso Berning et al. (1980); van der Meer et al. (1986); Vorechovsky et al. (1993)

entryList

entry status live allelicVariantExists true epochCreated 963471600 geneMap geneSymbols ANKH, HANK, ANK, CMDJ, CCAL2, CPPDD sequenceID 3909 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 605145 phenotypeInheritance Autosomal dominant phenotype Chondrocalcinosis 2 phenotypeMimNumber 118600 phenotypeMappingKey 3 mimNumber 605145 phenotypeInheritance Autosomal dominant phenotype Craniometaphyseal dysplasia phenotypeMimNumber 123000 chromosomeLocationStart 14704908 chromosomeSort 51 chromosomeSymbol 5 mimNumber 605145 geneInheritance None confidence C mappingMethod R, Fd geneName Ank, mouse, homolog of mouseMgiID MGI:3045421 mouseGeneSymbol Ank computedCytoLocation 5p15.2 cytoLocation 5p15.2-p14.1 transcript uc003jfm.4 chromosomeLocationEnd 14871886 chromosome 5 contributors Matthew B. Gross - updated : 03/26/2014 Patricia A. Hartz - updated : 3/25/2014 Marla J. F. O'Neill - updated : 11/9/2012 Cassandra L. Kniffin - updated : 11/10/2010 Victor A. McKusick - updated : 11/28/2006 Marla J. F. O'Neill - updated : 5/26/2004 Victor A. McKusick - updated : 5/3/2004 Victor A. McKusick - updated : 10/29/2002 Victor A. McKusick - updated : 11/14/2001 Victor A. McKusick - updated : 6/20/2001 Victor A. McKusick - updated : 4/18/2001 clinicalSynopsisExists false mimNumber 605145 allelicVariantList allelicVariant status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs121908405 text In 2 apparently unrelated German families with craniometaphyseal dysplasia ({123000}), previously reported by {14:Spranger et al. (1965)} and {13:Schwahn et al. (1996)}, {9:Nurnberg et al. (2001)} found deletion of 3 basepairs leading to deletion of codon 377 (phenylalanine). Because of different haplotype backgrounds, these were thought to be recurrent mutations, an interpretation favored by a short tandem repeat structure for F377del (1196delCTT). {12:Reichenberger et al. (2001)} reported the same mutation in affected members of 2 families with craniometaphyseal dysplasia. They designated the mutation PHE376DEL (1127delTCT) based on a different numbering system. mutations ANKH, PHE377DEL number 1 clinvarAccessions RCV000005501;;1 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs28939080 text In a Swiss family and an Australian family with craniometaphyseal dysplasia (CMDD; {123000}), the latter family originally reported by {15:Taylor and Sprague (1989)}, {9:Nurnberg et al. (2001)} identified a gly389-to-arg (G389R) missense mutation in the ANKH gene as the basis of craniometaphyseal dysplasia. That these were recurrent mutations was supported by the fact that they were on different haplotype backgrounds and by the nature of the affected sequence, namely, a CpG dinucleotide for G389R (1233G-A). {2:Baynam et al. (2009)} restudied the Australian family with CMDD that was originally reported by {15:Taylor and Sprague (1989)} and found evidence for chondrocalcinosis segregating with CMDD in mutation-positive female family members. Although a chance association of chondrocalcinosis with CMDD could not be excluded, {2:Baynam et al. (2009)} suggested that the lack of joint symptoms in affected male family members might be due to involvement of sex-dependent mechanisms or to the fact that only mutation-positive women in the pedigree had reached the age at which the chondrocalcinosis phenotype typically expresses. mutations ANKH, GLY389ARG number 2 alternativeNames CHONDROCALCINOSIS 2, INCLUDED clinvarAccessions RCV000032998;;1;;;RCV000005502;;1 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT text In a patient with craniometaphyseal dysplasia ({123000}), {9:Nurnberg et al. (2001)} identified an insertion of a single alanine in the ANKH cDNA; the mutation, however, was an A-to-G transition in the splice acceptor site of intron 9 that ended with a split codon, which contributed to the codon (GCA) for the extra alanine. A new splice acceptor site in the disease allele was created by the heterozygous point mutation at position -4 of the splice donor site of intron 9. {12:Reichenberger et al. (2001)} identified the same mutation in affected members of a family with craniometaphyseal dysplasia. mutations ANKH, IVS9, A-G, -4 number 3 clinvarAccessions RCV000005503;;1 status moved number 4 name MOVED TO {605145.0001} movedTo 605145.0001 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs121908406 text In 2 affected members of a family with craniometaphyseal dysplasia ({123000}), {9:Nurnberg et al. (2001)} identified a 3-bp deletion (1192delCTT) in exon 9 of the ANKH gene, resulting in the deletion of ser375. In 2 sporadic cases of craniometaphyseal dysplasia, {12:Reichenberger et al. (2001)} found the same 3-bp deletion, which they designated 1122delCTC based on a different numbering system. mutations ANKH, SER375DEL number 5 clinvarAccessions RCV000005504;;1 status live name CHONDROCALCINOSIS 2 dbSnps rs121908407 text In a French family with chondrocalcinosis-2 ({118600}) reported by {1:Andrew et al. (1999)}, {11:Pendleton et al. (2002)} found that affected members were heterozygous for a 143T-C transition in exon 2 of the ANKH gene, resulting in a met48-to-thr (M48T) substitution. The mutation is in a transmembrane domain at a position that is absolutely conserved in the ANKH protein over 400 million years of evolution from fish to mammals. mutations ANKH, MET48THR number 6 clinvarAccessions RCV000005505;;1 status live name CHONDROCALCINOSIS 2 text In a British family with chondrocalcinosis-2 ({118600}) reported by {7:Hughes et al. (1995)}, {11:Pendleton et al. (2002)} found that affected members were heterozygous for a -11C-T change located 11-bp upstream of the normal ATG initiation codon of the ANKH gene. This change generated an alternative ATG initiation codon and added 4 amino acids to the highly conserved N terminus of the ANKH protein. mutations ANKH, -11C-T number 7 clinvarAccessions RCV000005506;;1 status live name CHONDROCALCINOSIS 2, SPORADIC dbSnps rs121908408 text In 1 of 95 British patients with sporadic chondrocalcinosis-2 ({118600}), {11:Pendleton et al. (2002)} identified a 3-bp deletion in exon 12 of the ANKH gene that deleted a glutamate residue (E490del) located 3 amino acids from the highly conserved C terminus of the ANKH protein. The 79-year-old proband had a sister who had undergone bilateral knee replacements for 'osteoarthritis.' The sister and son of the proband were heterozygous for this ANKH mutation, but the son was not yet old enough for a reliable diagnosis of chondrocalcinosis. mutations ANKH, GLU490DEL number 8 clinvarAccessions RCV000005507;;1 status live name CHONDROCALCINOSIS 2 dbSnps rs121908409 text In a family with autosomal dominant familial calcium pyrophosphate dihydrate deposition disease ({118600}), {17:Williams et al. (2002)} identified a C-to-T transition at 14 bp from the start codon of the ANKH gene, resulting in a pro5-to-leu (P5L) change, which segregated with the disease. Some members of the family with the disease haplotype were considered too young to manifest the disorder; some other members of the family did not have the disease haplotype but were apparently affected. mutations ANKH, PRO5LEU number 9 clinvarAccessions RCV000005508;;1 status live name CHONDROCALCINOSIS 2 dbSnps rs121908410 text {16:Williams et al. (2003)} screened 2 US families with autosomal dominant calcium pyrophosphate dihydrate deposition disease ({118600}) for mutations in the ANKH gene and found that all affected members were heterozygous for a pro5-to-thr (P5T) mutation. They noted that another mutation at the same codon (P5L; {605145.0009}) had previously been reported to cause the same disorder and suggested that the evolutionarily conserved P5 position of ANKH may represent a hotspot for mutation in families with autosomal dominant CPPDD. mutations ANKH, PRO5THR number 10 clinvarAccessions RCV000005509;;1 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs267606656 text In a French boy with craniometaphyseal dysplasia ({123000}), {8:Kornak et al. (2010)} identified a heterozygous 1015T-C transition in exon 9 of the ANKH gene, resulting in a cys339-to-arg (C339R) substitution in a highly conserved residue in transmembrane helix 9. The patient had a severe form of the disorder, with hearing loss and bilateral facial palsy developing soon after birth. He had severe sclerosis of the skull base, orbits, maxilla, and mandible, with almost complete obstruction of the sinuses. There was rapid worsening of the bone phenotype in the first years of life. mutations ANKH, CYS339ARG number 11 clinvarAccessions RCV000005510;;1 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs267606658 text In a 24-year-old man from the Netherlands with craniometaphyseal dysplasia ({123000}), {8:Kornak et al. (2010)} identified a heterozygous 1172T-C transition in exon 10 of the ANKH gene, resulting in a leu391-to-pro (L391P) substitution in a highly conserved residue in the loop between transmembrane helices 10 and 11. The patient presented with progressive conductive and sensorineural hearing loss and was found to have typical features of the disorder, with unilateral facial palsy apparent in infancy, macrocephaly, and teeth crowding. mutations ANKH, LEU391PRO number 12 clinvarAccessions RCV000005511;;1 status live name CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT dbSnps rs267606657 text In a 43-year-old Italian man with craniometaphyseal dysplasia ({123000}), {8:Kornak et al. (2010)} identified a heterozygous 1001T-G transversion in exon 8 of the ANKH gene, resulting in a leu334-to-arg (L334R) substitution in a highly conserved residue in transmembrane helix 9. The patient had typical manifestations of CMD, with sclerosis of the skull base and maxilla, hyperostotic but not sclerotic mandible, and partially obstructed sinuses without cranial nerve compression. He also had narrowing of the middle ear cavities with bilateral fixation of the body of the incus to the lateral attic, resulting in conductive deafness and tinnitus. These middle ear manifestations were similar to those observed in postinflammatory ossicular fixation secondary to acute or chronic otitis media. mutations ANKH, LEU334ARG number 13 clinvarAccessions RCV000005512;;1 prefix * titles alternativeTitles HANK preferredTitle ANK, MOUSE, HOMOLOG OF; ANKH textSectionList textSection textSectionTitle Description textSectionContent ANKH is a highly conserved transmembrane pyrophosphate transporter that channels intracellular pyrophosphate into extracellular matrix, where it acts as a potent inhibitor of mineralization ({3:Chen et al., 2011}). textSectionName description textSectionTitle Cloning textSectionContent Mutation at the mouse 'progressive ankylosis' (ank) locus causes a generalized, progressive form of arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction. {6:Ho et al. (2000)} showed that the ank locus encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Using a positional cloning approach, {6:Ho et al. (2000)} identified the mouse Ank gene. Using the exon/intron structure of the mouse gene and partial sequence from human EST clones, {6:Ho et al. (2000)} amplified and sequenced the complete coding region of human ANK. Orthologs of mouse Ank were also found in zebrafish, rat, and cow. The human ANK gene is virtually identical to mouse ank, with only 9 amino acid differences over a 492-amino acid protein. There are 3 potential N-linked glycosylation sites and multiple putative phosphorylation sites. A hydropathy analysis revealed 9 to 12 hydrophobic stretches, most approximately 20 residues long, as would be expected for membrane-spanning regions in an integral multipass transmembrane protein. Western blot analysis suggested that the ank protein is expressed at the cell surface. Northern blot analysis revealed that ank mRNA is expressed in many tissues in adult mice, including heart, brain, liver, spleen, lung, muscle, and kidney. textSectionName cloning textSectionTitle Gene Function textSectionContent Although soft tissue phenotypes had not been reported in ank mice, {6:Ho et al. (2000)} observed increased calcification in kidneys of adult mice, consistent with an important role for the gene in nonskeletal tissues. Fibroblasts from ank mutants displayed about a 2-fold increase in intracellular inorganic pyrophosphate levels over wildtype cells and there was a 3- to 5-fold decrease in extracellular pyrophosphate levels. Additional studies demonstrated that ANK functions through a probenecid-sensitive anion transport mechanism. {6:Ho et al. (2000)} suggested that these results identified ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. textSectionName geneFunction textSectionTitle Mapping textSectionContent By radiation hybrid mapping, {6:Ho et al. (2000)} mapped the human ANK gene to chromosome 5p, in a region showing homology of synteny with proximal mouse chromosome 15. {9:Nurnberg et al. (2001)} stated that the ANKH gene maps to chromosome 5p15.2-p14.1. {4:Gross (2014)} mapped the ANKH gene to chromosome 5p15.2 based on an alignment of the ANKH sequence (GenBank {GENBANK AF274753}) with the genomic sequence (GRCh37). textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Craniometaphyseal Dysplasia Craniometaphyseal dysplasia is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. An autosomal dominant form of the disorder (CMDD; {123000}) was mapped to 5p15.2-p14.1 ({10:Nurnberg et al., 1997}) within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene. The ANK protein spans the outer cell membrane and shuttles inorganic pyrophosphate, a major inhibitor of physiologic and pathologic calcification, bone mineralization, and bone resorption. {9:Nurnberg et al. (2001)} identified 6 different heterozygous mutations in the ANKH gene in 8 of 9 families with CMDD (see, e.g., {605145.0001}-{605145.0005}). The mutations predicted single amino acid substitutions, deletions, or insertions. Using a helix prediction program, they proposed for the ANK molecule 12 membrane-spanning helices with an alternate inside/out orientation and a central channel permitting the passage of inorganic pyrophosphate. The mutations occurred at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. The results linked the inorganic pyrophosphate channel ANK with bone formation and remodeling. {12:Reichenberger et al. (2001)} demonstrated 3 different mutations in the ANKH gene in 5 different families and in isolated cases of CMDD. All mutations clustered within 7 amino acids in 1 of the 6 possible cytosolic domains of the ANKH protein. These results suggested that the mutated protein has a dominant-negative effect on its function, since reduced levels of pyrophosphate in bone matrix increase mineralization. Progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in the long bones characterize CMD. Chondrocalcinosis-2 Chondrocalcinosis is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. {11:Pendleton et al. (2002)} showed that affected members of 2 previously described families with chondrocalcinosis-2 (CCAL2; {118600}), which is also called calcium pyrophosphate dihydrate deposition disease (CPPDD), had mutations in the ANKH gene. One of the mutations resulted in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment ({605145.0006}); the other created a new ATG start site that added 4 additional residues to the ANKH protein ({605145.0007}). In addition, 1 of 95 patients with sporadic chondrocalcinosis from the U.K. showed a deletion of a single codon in the ANKH gene ({605145.0008}). The same change was found in the patient's sister and son; the sister had bilateral knee replacement for osteoarthritis. Each of the 3 mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All 3 mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggested that small sequence changes in ANKH are 1 cause of chondrocalcinosis and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in CCAL2 families and mutant mice, and may provide a useful pharmacologic target for treating some forms of human chondrocalcinosis. In a family with calcium pyrophosphate dihydrate deposition disease, {17:Williams et al. (2002)} identified a pro5-to-leu ({605145.0009}) mutation in the ANKH gene. They postulated that loss of function of ANKH causes elevated extracellular inorganic pyrophosphate levels, predisposing to CCAL2 crystal deposition. {16:Williams et al. (2003)} screened for mutations in the ANKH gene in 2 U.S. families with autosomal dominant CPPDD and found that all affected members were heterozygous for a pro5-to-thr mutation ({605145.0010}). The 2 families displayed distinct haplotypes. {16:Williams et al. (2003)} noted that the family described by {17:Williams et al. (2002)} had a different mutation at the same codon (see {605145.0009}) and also displayed a distinct haplotype. They concluded that the evolutionarily conserved pro5 position of ANKH may represent a hotspot for mutation in families with autosomal dominant CCAL2. Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans. Ank encodes a multiple-pass transmembrane protein that regulates pyrophosphate levels inside and outside tissue culture cells; conflicting models have been proposed to explain the effects of the human mutations. {5:Gurley et al. (2006)} tested wildtype and mutant forms of ANK for radiolabeled pyrophosphate-transport activity in frog oocytes. They also reconstructed 2 human mutations in a bacterial artificial chromosome and tested them in transgenic mice for rescue of the Ank-null phenotype and for induction of new skeletal phenotypes. Wildtype ANK stimulates saturable transport of pyrophosphate ions across the plasma membrane, with half maximal rates attained at physiologic levels of pyrophosphate. Chondrocalcinosis mutations retain apparently wildtype transport activity and can rescue the joint-fusion phenotype of Ank-null mice. Craniometaphyseal dysplasia mutations do not transport pyrophosphate and cannot rescue the defects of Ank-null mice. Furthermore, microcomputed tomography revealed previously unappreciated phenotypes in Ank-null mice that are reminiscent of craniometaphyseal dysplasia. The combination of biochemical and genetic analyses provided insight into how mutations in ANKH cause human skeletal disease. In an Australian family with CMDD and a known mutation in the ANKH gene (G389R; {605145.0002}), {2:Baynam et al. (2009)} found evidence for chondrocalcinosis segregating with CMDD in mutation-positive female family members. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Mice carrying the progressive ankylosis mutation have been studied as a model of arthritis. The autosomal recessive Ank mutation causes an abnormal flat-footed gait in young mice due to decreased mobility of ankle and toe joints. Loss of joint mobility becomes more severe with age and spreads to most joints throughout the limbs and vertebral column leading to complete rigidity and death around 6 months of age. Hydroxyapatite crystals develop in articular surfaces and synovial fluid of Ank mice, accompanied by joint space narrowing, cartilage erosion, and formation of bony outgrowths or osteophytes that cause fusion (ankylosis) and joint immobility. {6:Ho et al. (2000)} identified a G-to-T substitution in the mouse Ank gene, leading to a nonsense mutation in exon 11, the penultimate exon of mouse Ank. This mutation truncates the C-terminal region of the protein and greatly reduces its activity in vitro. The mouse Ank gene is expressed in developing articular surfaces and may help maintain the unmineralized state by providing a local source of inorganic pyrophosphate to inhibit hydroxyapatite formation. In the absence of normal Ank activity, mineralization extends unhindered throughout articular cartilage, hydroxyapatite deposits form in synovial fluid, and new bone is deposited in and around joints, showing that the gene is essential for normal joint maintenance. {3:Chen et al. (2011)} created knockin (KI) mice overexpressing human ANK with the phe377 deletion ({605145.0001}) associated with craniometaphyseal dysplasia. Ank KI/KI mice exhibited increased bone mass in craniofacial bones, especially in mandibles, excessive trabecular bone in diaphyses of long bones, and hypomineralization of cortex of long bones. Metaphyses were undertrabeculated. Cultured Ank KI/KI calvarial osteoblasts and bone marrow stromal cells showed reduced mineral nodule formation compared with wildtype controls. Mature osteoclasts derived from Ank KI/KI bone marrow progenitors were reduced in size, showed a disrupted actin ring, produced fewer multinucleated osteoclasts, and displayed reduced cell migration. Extracellular pyrophosphate was normal in Ank KI/KI osteoblasts, apparently due to compensatory upregulation of Pc1 (ENPP1; {173335}), another regulator of extracellular pyrophosphate. {3:Chen et al. (2011)} found that peripheral blood mononuclear cells of adult craniometaphyseal dysplasia patients also showed defective osteoclastogenesis, with reduced number of multinucleated osteoclasts and reduced mineral resorption. textSectionName animalModel geneMapExists true editHistory mgross : 03/26/2014 mgross : 3/26/2014 mcolton : 3/25/2014 carol : 11/12/2012 terry : 11/9/2012 wwang : 11/15/2010 ckniffin : 11/10/2010 alopez : 11/28/2006 terry : 11/28/2006 carol : 5/26/2004 carol : 5/26/2004 carol : 5/26/2004 terry : 5/26/2004 tkritzer : 5/10/2004 terry : 5/3/2004 carol : 11/1/2002 carol : 11/1/2002 tkritzer : 10/30/2002 terry : 10/29/2002 carol : 11/14/2001 carol : 11/14/2001 cwells : 7/2/2001 cwells : 6/25/2001 terry : 6/20/2001 alopez : 4/27/2001 terry : 4/18/2001 carol : 4/9/2001 joanna : 8/3/2000 alopez : 7/13/2000 dateCreated Thu, 13 Jul 2000 03:00:00 EDT creationDate Ada Hamosh : 7/13/2000 epochUpdated 1395817200 dateUpdated Wed, 26 Mar 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61666-8 publisherName Elsevier Science title Refinement of the chromosome 5p locus for familial calcium pyrophosphate dihydrate deposition disease. mimNumber 605145 referenceNumber 1 publisherAbbreviation ES pubmedID 9915952 source Am. J. Hum. Genet. 64: 136-145, 1999. authors Andrew, L. J., Brancolini, V., Serrano de la Pena, L., Devoto, M., Caeiro, F., Marchegiani, R., Reginato, A., Gaucher, A., Netter, P., Gillet, P., Loeuille, D., Prockop, D. J., Carr, A., Wordsworth, B. F., Lathrop, M., Butcher, S., Considine, E., Everts, K., Nicod, A., Walsh, S., Williams, C. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.32875 publisherName John Wiley & Sons, Inc. title Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. (Letter) mimNumber 605145 referenceNumber 2 publisherAbbreviation Wiley pubmedID 19449425 source Am. J. Med. Genet. 149A: 1331-1333, 2009. authors Baynam, G., Goldblatt, J., Schofield, L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=21149338 publisherName HighWire Press title A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD). mimNumber 605145 referenceNumber 3 publisherAbbreviation HighWire pubmedID 21149338 source Hum. Molec. Genet. 20: 948-961, 2011. authors Chen, I.-P., Wang, L., Jiang, X., Aguila, H. L., Reichenberger, E. J. pubmedImages true publisherUrl http://highwire.stanford.edu source Baltimore, Md. 3/26/2014. mimNumber 605145 authors Gross, M. B. title Personal Communication. referenceNumber 4 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63464-8 publisherName Elsevier Science title Biochemical and genetic analysis of ANK in arthritis and bone disease. mimNumber 605145 referenceNumber 5 publisherAbbreviation ES pubmedID 17186460 source Am. J. Hum. Genet. 79: 1017-1029, 2006. authors Gurley, K. A., Reimer, R. J., Kingsley, D. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=10894769 publisherName HighWire Press title Role of the mouse ank gene in control of tissue calcification and arthritis. mimNumber 605145 referenceNumber 6 publisherAbbreviation HighWire pubmedID 10894769 source Science 289: 265-270, 2000. authors Ho, A. M., Johnson, M. D., Kingsley, D. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8528213 publisherName HighWire Press title Localisation of a gene for chondrocalcinosis to chromosome 5p. mimNumber 605145 referenceNumber 7 publisherAbbreviation HighWire pubmedID 8528213 source Hum. Molec. Genet. 4: 1225-1228, 1995. authors Hughes, A. E., McGibbon, D., Woodward, E., Dixey, J., Doherty, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.33301 publisherName John Wiley & Sons, Inc. title Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. mimNumber 605145 referenceNumber 8 publisherAbbreviation Wiley pubmedID 20358596 source Am. J. Med. Genet. 152A: 870-874, 2010. authors Kornak, U., Brancati, F., Le Merrer, M., Lichtenbelt, K., Hohne, W., Tinschert, S., Garaci, F. G., Dallapiccola, B., Nurnberg, P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/88236 publisherName Nature Publishing Group title Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. mimNumber 605145 referenceNumber 9 publisherAbbreviation NPG pubmedID 11326272 source Nature Genet. 28: 37-41, 2001. authors Nurnberg, P., Thiele, H., Chandler, D., Hohne, W., Cunningham, M. L., Ritter, H., Leschik, G., Uhlmann, K., Mischung, C., Harrop, K., Goldblatt, J., Borochowitz, Z. U., Kotzot, D., Westermann, F., Mundlos, S., Braun, H.-S., Laing, N., Tinschert, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)64200-1 publisherName Elsevier Science title The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5q and is distinct from the growth hormone-receptor gene. mimNumber 605145 referenceNumber 10 publisherAbbreviation ES pubmedID 9382103 source Am. J. Hum. Genet. 61: 918-923, 1997. authors Nurnberg, P., Tinschert, S., Mrug, M., Hampe, J., Muller, C. R., Fuhrmann, E., Braun, H.-S., Reis, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60376-0 publisherName Elsevier Science title Mutations in ANKH cause chondrocalcinosis. mimNumber 605145 referenceNumber 11 publisherAbbreviation ES pubmedID 12297987 source Am. J. Hum. Genet. 71: 933-940, 2002. authors Pendleton, A., Johnson, M. D., Hughes, A., Gurley, K. A., Ho, A. M., Doherty, M., Dixey, J., Gillet, P., Loeuille, D., McGrath, R., Reginato, A., Shiang, R., Wright, G., Netter, P., Williams, C., Kingsley, D. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61042-8 publisherName Elsevier Science title Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. mimNumber 605145 referenceNumber 12 publisherAbbreviation ES pubmedID 11326338 source Am. J. Hum. Genet. 68: 1321-1326, 2001. authors Reichenberger, E., Tiziani, V., Watanabe, S., Park, L., Ueki, Y., Santanna, C., Baur, S. T., Shiang, R., Grange, D. K., Beighton, P., Gardner, J., Hamersma, H., Sellars, S., Ramesar, R., Lidral, A. C., Sommer, A., Raposo do Amaral, C. M., Gorlin, R. J., Mulliken, J. B., Olsen, B. R. pubmedImages false publisherUrl http://www.elsevier.com/ source Monatsschr. Kinderheilkd. 144: 1073-1077, 1996. mimNumber 605145 authors Schwahn, B., Schaper, J., Herkenrath, P., Michel, O., Schonau, E. title Chronic recurrent multifocal osteomyelitis with MR correlation: a case report. referenceNumber 13 title Die kraniometaphysaere Dysplasie (Pyle). mimNumber 605145 referenceNumber 14 pubmedID 14322785 source Z. Kinderheilk. 93: 64-79, 1965. authors Spranger, J. W., Paulsen, K., Lehmann, W. pubmedImages false title Dominant craniometaphyseal dysplasia: a family study over five generations. mimNumber 605145 referenceNumber 15 pubmedID 2712793 source Australas. Radiol. 33: 84-89, 1989. authors Taylor, D. B., Sprague, P. pubmedImages false articleUrl http://dx.doi.org/10.1002/art.11133 publisherName John Wiley & Sons, Inc. title Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease. mimNumber 605145 referenceNumber 16 publisherAbbreviation Wiley pubmedID 13130483 source Arthritis Rheum. 48: 2627-2631, 2003. authors Williams, C. J., Pendleton, A., Bonavita, G., Reginato, A. J., Hughes, A. E., Peariso, S., Doherty, M., McCarty, D. J., Ryan, L. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60385-1 publisherName Elsevier Science title Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH. mimNumber 605145 referenceNumber 17 publisherAbbreviation ES pubmedID 12297989 source Am. J. Hum. Genet. 71: 985-991, 2002. authors Williams, C. J., Zhang, Y., Timms, A., Bonavita, G., Caeiro, F., Broxholme, J., Cuthbertson, J., Jones, Y., Marchegiani, R., Reginato, A., Russell, R. G. G., Wordsworth, B. P., Carr, A. J., Brown, M. A. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:3045421 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 530378856,170671715 nbkIDs NBK1461;;Craniometaphyseal Dysplasia, Autosomal Dominant dermAtlas false hprdIDs 05509 swissProtIDs Q9HCJ1 zfinIDs ZDB-GENE-030131-2458,ZDB-GENE-050913-33 uniGenes Hs.156727 refSeqAccessionIDs NG_008273.1 gtr true cmgGene false ensemblIDs ENSG00000154122,ENST00000284268 umlsIDs C1423529 genbankNucleotideSequences 33878662,37182128,62896820,148171524,123998260,148171525,15042801,19733241,78403514,148171523,9502216,10047236,16549603,511818275,511818277,34527530,511818276,33988513,7023298,20043098,164693217,123984336,28626627,22707044,74230035 geneTests true approvedGeneSymbols ANKH geneIDs 56172 proteinSequences 15778896,16905507,37182129,578809944,17366849,62896821,123998261,123984337,14602635,119628439,119628440,9502217,189054654,10047237,193786000 geneticsHomeReferenceIDs gene;;ANKH;;ANKH

entryList

entry status live allelicVariantExists true epochCreated 662889600 geneMap geneSymbols GP9 sequenceID 2978 phenotypeMapList phenotypeMap phenotypeMimNumber 231200 mimNumber 173515 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 231200 phenotypeMappingKey 3 phenotype Bernard-Soulier syndrome, type C chromosomeLocationStart 128775458 chromosomeSort 524 chromosomeSymbol 3 mimNumber 173515 geneInheritance None confidence P mappingMethod REb, REc geneName Glycoprotein IX, platelet mouseMgiID MGI:1860137 mouseGeneSymbol Gp9 computedCytoLocation 3q21.3 cytoLocation 3q21 transcript uc003elm.2 chromosomeLocationEnd 128781253 chromosome 3 contributors Victor A. McKusick - updated : 11/26/2003 Cassandra L. Kniffin - reorganized : 6/24/2003 Cassandra L. Kniffin - updated : 6/20/2003 Victor A. McKusick - updated : 5/18/2001 Victor A. McKusick - updated : 3/24/1999 Victor A. McKusick - updated : 8/25/1997 clinicalSynopsisExists false mimNumber 173515 allelicVariantList allelicVariant status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs5030764 text In a rare case of variant Bernard-Soulier syndrome ({231200}) showing a pronounced imbalance in the expression of GP IX in relation to the GP Ib-alpha, GP Ib-beta, and GP V chains of the platelet membrane glycoprotein complex, {2:Clemetson et al. (1994)} identified homozygosity for an A-to-G transition resulting in an asn45-to-ser (N45S) substitution within the leucine-rich domain of the glycoprotein IX molecule. No mutations were found in GP Ib-alpha. The mutation created a new cleavage site for the restriction enzyme Fnu4HI. The substitution did not affect glycosylation at the neighboring asn44. The patient, a 23-year-old man, had a lifelong bleeding problem, including epistaxis. He was thrombocytopenic since childhood, with a platelet count of 30,000 to 60,000/microliter, and had a prolonged bleeding time. Peripheral blood smears showed giant platelets. {10:Sachs et al. (2003)} studied blood samples from 4 unrelated German patients with Bernard-Soulier syndrome living in different federal states. All were found to have the N45S mutation. {10:Sachs et al. (2003)} commented that the N45S mutation had been identified in British, Austrian, Swedish, Belgian, and multiple Finnish patients, and suggested that it may be an ancient mutation shared by northern and central European populations. They also commented that Bernard-Soulier syndrome is often misdiagnosed as immune thrombocytopenia; this was the case in 3 of the 4 patients they reported. mutations GP9, ASN45SER number 1 clinvarAccessions RCV000014484;;1 status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs121918036 text {11:Wright et al. (1993)} reported a family with classic Bernard-Soulier syndrome ({231200}) in which lesions of the GP1BA gene were excluded. On the other hand, they found compound heterozygosity for 2 different mutations of the GP9 gene: an A-to-G transition in codon 21, resulting in conversion of an aspartic acid to glycine (D21G), and an A-to-G transition in codon 45, converting an asparagine residue to serine ({173515.0001}). The alterations occurred in conserved residues in or flanking the GP IX leucine-rich glycoprotein motif. Both mutations created new recognition sites for the restriction enzyme Fnu4HI (isoschizomer, BsoFI). In screening 120 alleles in 60 normal subjects for Fnu4HI restriction, {11:Wright et al. (1993)} did not detect the mutations in any subjects other than direct relatives of the affected sibs. mutations GP9, ASP21GLY number 2 clinvarAccessions RCV000014485;;1 status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs121918037 text {8:Noris et al. (1997)} investigated the molecular basis of a case of Bernard-Soulier syndrome ({231200}) with deficient expression of GP IX, as detected by immunofluorescence studies. Nucleotide sequence analysis of the coding region showed a homozygous point mutation predicting a phenylalanine-to-serine substitution at position 55 (F55S) of the mature GP IX polypeptide within its unique leucine-rich repeat. By allele-specific oligonucleotide hybridization, they confirmed the homozygosity of the patient as well as the heterozygous state of 3 of his children studied. The parents of the patient, who were first cousins, were not available for study. mutations GP9, PHE55SER number 3 clinvarAccessions RCV000014486;;1 status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs28933377 text In a family with Bernard-Soulier syndrome ({231200}), {7:Noris et al. (1998)} identified a homozygous 1811T-C transition in the GP9 gene, resulting in a leu40-to-pro substitution (L40P), in a brother and sister affected by severe bleeding diathesis. Members of the family with mild bleeding diathesis and/or giant platelets in peripheral blood were heterozygous for the mutation, whereas the healthy members were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the 2 severely affected patients. mutations GP9, LEU40PRO number 4 clinvarAccessions RCV000014487;;1 status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs28933378 text In a Pakistani boy with Bernard-Soulier syndrome ({231200}), {9:Rivera et al. (2001)} identified a homozygous 1717T-C transition in the GP9 gene, resulting in a cys8-to-arg (C8R) missense mutation. The 2.5-year-old patient was evaluated for a lifelong history of easy bruising, prolonged bleeding from lacerations, and low platelet counts, first noted at the age of 2 months. The parents were consanguineous. mutations GP9, CYS8ARG number 5 clinvarAccessions RCV000014488;;1 status live name BERNARD-SOULIER SYNDROME, TYPE C dbSnps rs121918038 text In a man whose case history had been published by {1:Bernard et al. (1957)} and who represented the second case of Bernard-Soulier syndrome ({231200}), {5:Lanza et al. (2002)} found a homozygous T-to-C transition at position 1667 of the glycoprotein IX (GP IX) gene resulting in a leu7-to-pro (L7P) mutation in the signal peptide of the protein. This mutation was said to have been the only known example, up to that time, of a leader sequence defect in Bernard-Soulier syndrome. The mutation presumably led to an abnormal conformation and, hence, incorrect insertion of GP IX into the endoplasmic reticulum and/or to defective signal peptide cleavage, both of which are required for correct transport to the cell membrane. mutations GP9, LEU7PRO number 6 clinvarAccessions RCV000014489;;1 prefix * titles alternativeTitles PLATELET GLYCOPROTEIN IX;; GP IX preferredTitle GLYCOPROTEIN IX, PLATELET; GP9 textSectionList textSection textSectionTitle Description textSectionContent Platelet glycoprotein IX (GP9) is a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib (GP Ib), a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor (VWF; {613160}). The main portion of the receptor is a heterodimer composed of 2 polypeptide chains, an alpha chain (GP1BA; {606672}) and a beta chain (GP1BB; {138720}), that are linked by disulfide bonds. The complete receptor complex includes noncovalent association of the alpha and beta subunits with GP9 and platelet glycoprotein V (GP5; {173511}) (review by {6:Lopez et al., 1998}). textSectionName description textSectionTitle Cloning textSectionContent Using antibody screening of a human erythroleukemia cell (HEL) cDNA library, {4,3:Hickey et al. (1989, 1990)} cloned a cDNA that encodes GP IX and determined its nucleotide sequence. The predicted 165-amino acid protein has a molecular mass of about 17 kD and includes a 24-amino acid leucine-rich glycoprotein (LRG) segment. Leucine-rich segments are also found in the GP Ib alpha chain, beta chain, and GP5. Hydropathy analysis indicated that GP IX is a transmembrane protein with an extracellular region of 134 residues, and an intracytoplasmic region of 6 residues. {4:Hickey et al. (1989)} suggested that the GP9 protein may provide for membrane insertion and orientation of the larger component of the complex, GP Ib. textSectionName cloning textSectionTitle Mapping textSectionContent By hybridization of GP9 cDNA to sorted human chromosomes, {3:Hickey et al. (1990)} localized the GP9 gene to chromosome 3. By fluorescence in situ hybridization, {12:Yagi et al. (1995)} mapped the GP9 gene to 3q21. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent In a family with a variant of Bernard-Soulier syndrome (BSS; {231200}), characterized by a pronounced imbalance in the expression of GP IX in relation to the GP Ib-alpha, GP Ib-beta, and GP V chains of the platelet membrane glycoprotein complex, {2:Clemetson et al. (1994)} identified homozygosity for a mutation in the GP9 gene ({173515.0001}). textSectionName molecularGenetics geneMapExists true editHistory carol : 10/04/2010 ckniffin : 8/31/2010 carol : 6/13/2008 tkritzer : 12/2/2003 terry : 11/26/2003 carol : 6/24/2003 ckniffin : 6/20/2003 tkritzer : 12/12/2002 terry : 12/6/2002 mcapotos : 5/25/2001 terry : 5/18/2001 mcapotos : 4/26/2000 mgross : 4/2/1999 mgross : 3/31/1999 terry : 3/24/1999 alopez : 8/18/1998 jenny : 8/28/1997 terry : 8/25/1997 carol : 6/27/1996 mark : 6/26/1995 carol : 1/30/1995 supermim : 3/16/1992 carol : 5/9/1991 carol : 5/8/1991 carol : 1/3/1991 dateCreated Thu, 03 Jan 1991 03:00:00 EST creationDate Victor A. McKusick : 1/3/1991 epochUpdated 1286175600 dateUpdated Mon, 04 Oct 2010 03:00:00 EDT referenceList reference source Revue Francaise D'hematologie 12: 222-249, 1957. mimNumber 173515 authors Bernard, J., Caen, J., Maroteaux, P. title La dystrophie thrombocytaire hemorragipare congenitale. referenceNumber 1 articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=8049428 publisherName HighWire Press title Variant Bernard-Soulier syndrome associated with a homozygous mutation in the leucine-rich domain of glycoprotein IX. mimNumber 173515 referenceNumber 2 publisherAbbreviation HighWire pubmedID 8049428 source Blood 84: 1124-1131, 1994. authors Clemetson, J. M., Kyrle, P. A., Brenner, B., Clemetson, K. J. pubmedImages false publisherUrl http://highwire.stanford.edu title Human platelet glycoprotein IX: characterization of cDNA and localization of the gene to chromosome 3. mimNumber 173515 referenceNumber 3 pubmedID 2253772 source FEBS Lett. 274: 189-192, 1990. authors Hickey, M. J., Deaven, L. L., Roth, G. J. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2771955 publisherName HighWire Press title Human platelet glycoprotein IX: an adhesive prototype of leucine-rich glycoproteins with flank-center-flank structures. mimNumber 173515 referenceNumber 4 publisherAbbreviation HighWire pubmedID 2771955 source Proc. Nat. Acad. Sci. 86: 6773-6777, 1989. authors Hickey, M. J., Williams, S. A., Roth, G. J. pubmedImages false publisherUrl http://highwire.stanford.edu title A leu7-to-pro mutation in the signal peptide of platelet glycoprotein (GP)IX in a case of Bernard-Soulier syndrome abolishes surface expression of the GPIb-V-IX complex. mimNumber 173515 referenceNumber 5 pubmedID 12100158 source Brit. J. Haemat. 118: 260-266, 2002. authors Lanza, F., de la Salle, C., Baas, M.-J., Schwartz, A., Boval, B., Cazenave, J.-P., Caen, J. P. pubmedImages false articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9616133 publisherName HighWire Press title Bernard-Soulier syndrome. mimNumber 173515 referenceNumber 6 publisherAbbreviation HighWire pubmedID 9616133 source Blood 91: 4397-4418, 1998. authors Lopez, J. A., Andrews, R. K., Afshar-Kharghan, V., Berndt, M. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=1998&volume=103&issue=4&spage=1004 publisherName Blackwell Publishing title A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. mimNumber 173515 referenceNumber 7 publisherAbbreviation Blackwell pubmedID 9886312 source Brit. J. Haemat. 103: 1004-1013, 1998. authors Noris, P., Arbustini, E., Spedini, P., Belletti, S., Balduini, C. L. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title A phenylalanine-55 to serine amino-acid substitution in the human glycoprotein IX leucine-rich repeat is associated with Bernard-Soulier syndrome. mimNumber 173515 referenceNumber 8 pubmedID 9163595 source Brit. J. Haemat. 97: 312-320, 1997. authors Noris, P., Simsek, S., Stibbe, J., von dem Borne, A. E. G. K. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=2001&volume=112&issue=1&spage=105 publisherName Blackwell Publishing title Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome. mimNumber 173515 referenceNumber 9 publisherAbbreviation Blackwell pubmedID 11167791 source Brit. J. Haemat. 112: 105-108, 2001. authors Rivera, C. E., Villagra, J., Riordan, M., Williams, S., Lindstrom, K. J., Rick, M. E. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Bernard-Soulier syndrome due to the homozygous asn-45ser mutation in GPIX: an unexpected, frequent finding in Germany. mimNumber 173515 referenceNumber 10 pubmedID 14510954 source Brit. J. Haemat. 123: 127-131, 2003. authors Sachs, U. J. H., Kroll, H., Matzdorff, A. C., Berghofer, H., Lopez, J. A., Santoso, S. pubmedImages false articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=8481514 publisherName HighWire Press title Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome. mimNumber 173515 referenceNumber 11 publisherAbbreviation HighWire pubmedID 8481514 source Blood 81: 2339-2347, 1993. authors Wright, S. D., Michaelides, K., Johnson, D. J. D., West, N. C., Tuddenham, E. G. D. pubmedImages false publisherUrl http://highwire.stanford.edu title Human platelet glycoproteins V and IX: mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. mimNumber 173515 referenceNumber 12 pubmedID 8519770 source Biochemistry 34: 16132-16137, 1995. authors Yagi, M., Edelhoff, S., Disteche, C. M., Roth, G. J. pubmedImages false externalLinks mgiIDs MGI:1860137 mgiHumanDisease false ncbiReferenceSequences 208609983,530374449 refSeqAccessionIDs NG_008715.1 dermAtlas false hprdIDs 01432 swissProtIDs P14770 umlsIDs C1439350 uniGenes Hs.1144 gtr true cmgGene false ensemblIDs ENSG00000169704,ENST00000307395 genbankNucleotideSequences 311460881,511853216,19589327,124000290,74230053,2704480,123993322,24418008,2160045,340362,2804251,1644267,550553669,148171241,20988413,148171242,1772612 geneTests true approvedGeneSymbols GP9 geneIDs 2815 proteinSequences 311460882,124000291,123993323,4504077,119599691,340363,2160046,530374450,1644268,2822110,2804252,550553670,1772613,20988414 nextGxDx true locusSpecificDBs http://www.bernardsoulier.org/index.html;;Bernard-Soulier Syndrome database

entryList

entry status live allelicVariantExists true epochCreated 827136000 geneMap geneSymbols CYP2C9 sequenceID 7621 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 601130 phenotypeInheritance None phenotype Tolbutamide poor metabolizer phenotypeMappingKey 3 mimNumber 601130 phenotypeInheritance Autosomal dominant phenotype Warfarin sensitivity phenotypeMimNumber 122700 chromosomeLocationStart 96698349 chromosomeSort 349 chromosomeSymbol 10 mimNumber 601130 geneInheritance None confidence C mappingMethod REn, H geneName Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 9 mouseMgiID MGI:1919553,MGI:1917138 mouseGeneSymbol Cyp2c65,Cyp2c66 computedCytoLocation 10q23.33 cytoLocation 10q24 transcript uc001kka.4 chromosomeLocationEnd 96749485 chromosome 10 contributors Patricia A. Hartz - updated : 2/24/2011 Cassandra L. Kniffin - updated : 10/26/2010 Cassandra L. Kniffin - updated : 11/19/2009 Ada Hamosh - updated : 3/12/2009 Victor A. McKusick - updated : 1/9/2007 Marla J. F. O'Neill - updated : 8/23/2006 Marla J. F. O'Neill - updated : 11/11/2005 Marla J. F. O'Neill - updated : 9/2/2005 Cassandra L. Kniffin - updated : 6/9/2005 Victor A. McKusick - updated : 3/15/2005 Victor A. McKusick - updated : 11/26/2003 Ada Hamosh - updated : 7/24/2003 Victor A. McKusick - updated : 6/26/2002 Victor A. McKusick - updated : 12/5/2001 Victor A. McKusick - updated : 5/10/2001 Victor A. McKusick - updated : 1/10/2001 Victor A. McKusick - updated : 12/11/2000 Ada Hamosh - updated : 6/15/2000 Victor A. McKusick - updated : 6/18/1999 Victor A. McKusick - updated : 5/14/1999 Victor A. McKusick - updated : 6/25/1997 clinicalSynopsisExists false mimNumber 601130 allelicVariantList allelicVariant status live name TOLBUTAMIDE POOR METABOLIZER dbSnps rs1057910 text The ile359-to-leu (I359L) substitution results from a 1075A-C transversion in the CYP2C9 gene and is also known as {dbSNP rs1057910} and CYP2C9*3. The variant leads to reduced warfarin metabolism and increased risk of bleeding ({15:Ross et al., 2010}). Extensive interindividual variation in the response to a given dose {19:Sullivan-Klose et al. (1996)} demonstrated that the form of CYP2C9 in which ile359 is replaced by leucine is the basis of poor metabolizing of tolbutamide, the sulfonylurea hypoglycemic agent used in the treatment of diabetes mellitus (NIDDM; {125853}). The frequency of the leu359 allele was found to be 0.06 in the Caucasian-American population and 0.005 in African Americans. The frequency of the leu359 allele was 0.026 in Chinese-Taiwanese. They found that the leu359 allelic variant of CYP2C9 also has a lower affinity and a lower intrinsic clearance for S-warfarin 7-hydroxylation than the ile359 variant. Presumably, 7-hydroxylation has an important role in terminating the anticoagulant activity of warfarin in vitro, and individuals who are homozygous for the leu359 variant might require lower doses of this anticoagulant. In a patient who was unusually sensitive to warfarin therapy (see {122700}), {18:Steward et al. (1997)} identified homozygosity for I359L, the so-called CYP2C9*3 allele. The patient, who was taking 0.5 mg of warfarin daily, had an S-to-R enantiomer ratio of 3.9:1, whereas control patients taking 4 to 8 mg of warfarin daily had S-to-R ratios of about 0.5:1. {18:Steward et al. (1997)} concluded that expression of CYP2C9*3 is associated with diminished clearance of the more potent S-warfarin, and that analysis of the plasma S-to-R warfarin ratio might serve as a useful alternative test to genotyping. {8:Kidd et al. (1999)} described a 29-year-old male Caucasian who had participated in 6 bioequivalence studies over a period of several years. The patient displayed severe hypoglycemia after a single dose of glipizide, a second generation sulfonylurea structurally similar to tolbutamide and used as an oral hypoglycemic agent. His oral clearance of phenytoin was 21% of the mean of 11 other individuals, and his oral clearance of glipizide was only 18% of the mean of 10 other individuals. His oral clearance of nifedipine (a CYP3A4 ({124010}) substrate) and chlorpheniramine (a CYP2D6 (see {124030}) substrate) did not differ from that of other individuals studied. Genotype testing demonstrated that the individual was homozygous for the leu359 allele and did not possess any of the known defective CYP2C19 ({124020}) alleles. These studies established that the leu359 allele is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype. In a study of 281 epileptic patients treated with phenytoin, {20:Tate et al. (2005)} found a significant association between the maximum dose needed and the CYP2C9*3 allele (I359L). Mean phenytoin doses for individuals with 0, 1, or 2 copies of the *3 allele were 354, 309, and 250 mg, respectively, indicating a trend of reduction in maximum dose needed to control symptoms. {15:Ross et al. (2010)} genotyped 963 individuals from 7 geographic regions for the CYP2C9*3 variant. The highest frequencies were observed in Europe (4 to 21%), the Middle East (3 to 11%) and Central/South Asia (5 to 15%). The allele was not observed in Africa or most populations from the Americas, except the Pima (7%). In Oceania, the allele was not present in Melanesians, but in Papua New Guinea the frequency was 12%. The allele was absent in many populations in East Asia, but reached frequencies of 10% or higher in some populations, such as the Tu, Tujia and Xibo. Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry. mutations CYP2C9, ILE359LEU ({dbSNP rs1057910}) number 1 alternativeNames WARFARIN SENSITIVITY, INCLUDED;; PHENYTOIN POOR METABOLIZER, INCLUDED;; GLIPIZIDE POOR METABOLIZER, INCLUDED clinvarAccessions RCV000008917;;1;;;RCV000008916;;1;;;RCV000008919;;1;;;RCV000008918;;1 status live name WARFARIN SENSITIVITY dbSnps rs1799853 text The arg144-to-cys (R144C) substitution results from a 430C-T transition in the CYP2C9 gene and is also known as {dbSNP rs1799853} and CYP2C9*2. The variant leads to reduced warfarin metabolism and increased risk of bleeding ({15:Ross et al., 2010}). Extensive interindividual variation in the response to a given dose of warfarin (coumarin) makes the prediction of an accurate maintenance dose difficult, with an effective daily dose ranging from 0.5 to 60 mg. The asymmetric carbon of warfarin (C9) gives rise to 2 enantiomeric forms, R-warfarin and S-warfarin, which are differentially metabolized. When administered as a racemate, S-warfarin is about 3 times as potent as R-warfarin. CYP2C9 is the principal enzyme that catalyzes the conversion of S-warfarin to inactive 6-hydroxy and 7-hydroxy metabolites, whereas the oxidative metabolism of R-warfarin is mainly catalyzed by CYP1A2 ({124060}) and CYP3A4 ({124010}). In addition to the wildtype CYP2C9*1 allele, point mutations in the CYP2C9 gene result in 2 allelic variants: CYP2C9*2, where cysteine substitutes for arginine at amino acid 144, and CYP2C9*3, where leucine substitutes for isoleucine at residue 359 ({601130.0001}). Both allelic variants have impaired hydroxylation of S-warfarin when expressed in vitro; the CYP2C9*3 variant is less than 5% as efficient as the wildtype enzyme, while CYP2C9*2 shows about 12% of wildtype activity, apparently as a result of the amino acid substitution altering the interaction of the enzyme with cytochrome P450 oxidoreductase. {1:Aithal et al. (1999)} studied the frequency of the 2 variant alleles in individuals with a low warfarin dose requirement; see {122700}. Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy and had an increased risk of major bleeding complications. {9:King et al. (2004)} concluded that the coding region nonsynonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 ({601130.0001}) alleles are the major CYP2C9-related factors affecting warfarin dose in U.K. Caucasians. Upstream CYP2C9 polymorphisms did not appear to be important independent determinants of dose requirement. In a metaanalysis of studies of the CYP2C9*2 and CYP2C9*3 ({601130.0001}) alleles, {16:Sanderson et al. (2005)} found that patients carrying these alleles had lower mean daily warfarin dosage and greater risk of bleeding. However, {13:Li et al. (2006)} could only partially confirm this. They found that polymorphisms in the VKORC1 gene ({608547}) were strongly associated with warfarin dosage requirement. They found no association with either of the 2 CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for the VKORC1*1173 polymorphism. {15:Ross et al. (2010)} genotyped 963 individuals from 7 geographic regions for the CYP2C9*2 and CYP2C9*3 variants. The CYP2C9*2 allele was primarily restricted to European (2 to 29%), Middle Eastern (11 to 20%) and Central/South Asia populations (2 to 16%), and was mostly absent in other population groups, such as Africa and the Middle East. Exceptions included the North Eastern Bantu from Africa (4%), the Yakut from East Asia (2%) and the Maya (2%). Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry. mutations CYP2C9, ARG144CYS ({dbSNP rs1799853}) number 2 clinvarAccessions RCV000008920;;1 status live name WARFARIN SENSITIVITY dbSnps rs72558191 text The arg144-to-cys polymorphism of CYP2C9 ({601130.0002}), associated with warfarin sensitivity in Caucasian subjects, is very rare in Chinese. {12:Leung et al. (2001)} studied CYP2C9 polymorphisms in 89 Chinese patients receiving warfarin. They found genetic polymorphisms in exon 4 and at codon 208; most were heterozygous leu208-to-val and homozygous val208. Homozygous leu208, a common allele in Caucasians, was uncommon in this cohort. Subjects heterozygous for leu208 to val or homozygous for val208 appeared to have a lower warfarin dose requirement than those carrying homozygous leu208. The authors stated that 'at codon 208, polymorphic alleles existed at high frequency and appeared to have lower warfarin dose requirements.' mutations CYP2C9, LEU208VAL number 3 clinvarAccessions RCV000008921;;1 prefix * titles preferredTitle CYTOCHROME P450, SUBFAMILY IIC, POLYPEPTIDE 9; CYP2C9 textSectionList textSection textSectionTitle Description textSectionContent CYP2C9 is one of the major drug-metabolizing CYP450 isoforms. See {124020} for more information. textSectionName description textSectionTitle Biochemical Features textSectionContent Crystal Structure {22:Williams et al. (2003)} described the crystal structure of human CYP2C9, both unliganded and in complex with the anticoagulant drug warfarin (see {122700}). The structure defines unanticipated interactions between CYP2C9 and warfarin, and reveals a new binding pocket. The binding mode of warfarin suggests that CYP2C9 may undergo an allosteric mechanism during its function. The newly discovered binding pocket also suggests that CYP2C9 may simultaneously accommodate multiple ligands during its biologic function, and provides a possible molecular basis for understanding complex drug-drug interactions. textSectionName biochemicalFeatures textSectionTitle Gene Function textSectionContent In 16 patients with coronary artery disease and 5 healthy controls, {3:Fichtlscherer et al. (2004)} studied the effects of sulfaphenazole, a selective inhibitor of CYP2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) forearm blood flow responses. In patients with coronary artery disease, sulfaphenazole markedly and dose-dependently enhanced the forearm blood flow response to acetylcholine but not to sodium nitroprusside; there was no effect on either in the healthy controls. {3:Fichtlscherer et al. (2004)} stated that the enhancement of endothelium-dependent vasodilator responses by the CYP2C9 inhibitor in patients with coronary artery disease seemed to be related to an increase in the bioavailability of NO, which they suggested was due to an attenuated generation of reactive oxygen species by CYP2C9 in endothelial cells. textSectionName geneFunction textSectionTitle Mapping textSectionContent CYP2C9 is 1 of several CYP2C genes clustered in a 500-kb region on proximal 10q24 ({5:Gray et al., 1995}). {11:Kohn and Pelz (2000)} studied the warfarin-resistance locus of the rat, Rw, and by homology of synteny concluded that the homolog is on mouse chromosome 7 and 1 of 3 human chromosomes, including 10q25.3-q26. Using FISH, BAC end sequencing, and genomic database analysis, {4:Gough et al. (2003)} determined that the order of selected genes on chromosome 10q24, from centromere to telomere, is CYP2C9, PAX2 ({167409}), HOX11 (TLX1; {186770}), and NFKB2 ({164012}). textSectionName mapping textSectionTitle Molecular Genetics textSectionContent CYP2C9 is one of the primary P450 isozyme responsible for hydroxylation of tolbutamide, an oral sulfonylurea hypoglycemic agent used in the treatment of type II diabetes mellitus (NIDDM; {125853}). Population studies indicate the existence of rare (approximately 1 in 500) slow metabolizers of tolbutamide. {19:Sullivan-Klose et al. (1996)} sequenced the coding regions, intron-exon junctions, and upstream region of CYP2C9 in 2 slow metabolizers of tolbutamide. One individual was homozygous for ile359 to leu ({601130.0001}) and the other individual was heterozygous for arg144 to cys ({601130.0002}) and for ile359 to leu. No other genetic variations in CYP2C9 were detected in these individuals. PCR-RFLP tests showed that arg144/tyr358/ile359/gly417 is the principal CYP2C9 allele. Studies in a recombinant yeast expression system indicated that the leu359 allelic variant of CYP2C9 accounts for the occurrence of poor metabolizers of tolbutamide. The study also indicated that the leu359 allelic variant has a lower affinity and a lower intrinsic clearance for S-warfarin 7-hydroxylation than the wildtype ile359 variant. {21:Thum and Borlak (2000)} investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 2C9 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. {21:Thum and Borlak (2000)} concluded that expression of genes for cytochrome P450 monooxygenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs. Diclofenac is a nonsteroidal antiinflammatory drug that can cause rare but potentially serious hepatotoxicity. {2:Aithal et al. (2000)} found no evidence that polymorphism in CYP2C9 is a determinant of diclofenac-induced hepatotoxicity. {23:Wood (2001)} discussed pointers to genetic differences underlying racial differences in the response to drugs. CYP2C9 is the cytochrome P450 enzyme responsible for the metabolism of the isomer of warfarin (see {122700}) that is principally responsible for the anticoagulant effect of the drug. Two CYP2C9 alleles that produce a phenotype of poor metabolism occur in 11% and 8% of whites but only 3% and 0.8% of blacks ({24:Xie et al., 2001}). Such persons have impaired metabolism of warfarin and thus increased plasma concentrations of the drug. Persons with the genotype of impaired metabolism require lower doses of warfarin to achieve an anticoagulant effect similar to that in patients with the normal genotype ({1:Aithal et al., 1999}) and are more likely to have an excessive anticoagulant response. In addition, bleeding episodes tend to be more common in persons with the genotype of impaired metabolism. Patients with the CYP2C9*2 allele, R144C ({601130.0002}), and the CYP2C9*3 allele, I359L ({601130.0001}), require lower maintenance doses of warfarin because of the reduced activity of these common variants. {6:Higashi et al. (2002)} studied the association of these variants with over-anticoagulation and bleeding events during warfarin therapy in a retrospective cohort study. The results suggested that the 2 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. {10:Kirchheiner et al. (2003)} studied the effects of CYP2C9 on celecoxib, a nonsteroidal antiinflammatory drug (NSAID) that is used to treat rheumatoid arthritis and osteoarthritis and exhibits antiinflammatory, analgesic, and antipyretic activity by selective inhibition of cyclooxygenase-2 (COX2; {600262}). They found a more than 2-fold reduced oral clearance in homozygous carriers of CYP2C9*3; heterozygous carriers of 1 CYP2C9*3 allele were in between, whereas CYP2C9*2 had no significant influence on celecoxib pharmacokinetics. {10:Kirchheiner et al. (2003)} concluded that approximately 0.5% of Caucasians with a homozygous CYP2C9*3 genotype will have greatly increased internal exposure to celecoxib. It was not clear whether this is associated with greater efficacy or with an increased incidence and severity of adverse events. {14:Maekawa et al. (2006)} sequenced the CYP2C9 gene in 263 Japanese individuals (134 diabetics and 129 healthy volunteers) and identified 62 variations, 32 of which were novel. Only 5 haplotypes accounted for more than 87% of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. The authors noted that although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. {16:Sanderson et al. (2005)} presented a metaanalysis of studies of the CYP2C9*2 ({601130.0002}) and CYP2C9*3 ({601130.0001}) alleles. The {7:International Warfarin Pharmacogenetics Consortium (2009)} found that a pharmacogenetic dose algorithm for warfarin based on the genotype at VKORC1 ({608547}) and CYP2C9 accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and those who required 49 mg or more per week to achieve the targeted international normalized ratio than did a clinical algorithm alone (49.4% vs 33.3%, p less than 0.001, among patients requiring 21 mg or less per week; and 24.8% vs 7.2%, p less than 0.001, among those requiring 49 mg or more per week). The authors concluded that the use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation. {17:Speed et al. (2009)} found considerable geographic variation in frequencies of haplotypes spanning the CYP2C8 ({601129}) and CYP2C9 loci on chromosome 10q23-q24. More than 2,500 individuals from 45 populations worldwide were analyzed for 10 SNPs, including 8 in CYP2C8 and 2 in CYP2C9: 5 of the SNPs were changes in the coding region of the genes. The authors discussed the implications for the study of pharmacogenetics. textSectionName molecularGenetics geneMapExists true editHistory terry : 06/15/2012 terry : 6/6/2012 mgross : 2/24/2011 wwang : 2/16/2011 ckniffin : 10/26/2010 wwang : 12/10/2009 ckniffin : 11/19/2009 terry : 6/3/2009 alopez : 3/17/2009 alopez : 3/16/2009 terry : 3/12/2009 alopez : 1/10/2007 terry : 1/9/2007 terry : 11/16/2006 carol : 8/28/2006 terry : 8/23/2006 wwang : 11/11/2005 wwang : 9/2/2005 wwang : 7/21/2005 ckniffin : 6/9/2005 wwang : 3/18/2005 terry : 3/15/2005 tkritzer : 12/8/2003 tkritzer : 12/2/2003 terry : 11/26/2003 alopez : 8/29/2003 carol : 7/25/2003 carol : 7/25/2003 terry : 7/24/2003 cwells : 7/10/2002 terry : 6/26/2002 alopez : 12/13/2001 terry : 12/5/2001 terry : 5/22/2001 cwells : 5/18/2001 cwells : 5/16/2001 terry : 5/10/2001 cwells : 1/17/2001 terry : 1/10/2001 mcapotos : 12/28/2000 mcapotos : 12/18/2000 terry : 12/11/2000 alopez : 6/15/2000 carol : 8/4/1999 jlewis : 6/30/1999 terry : 6/18/1999 carol : 5/27/1999 mgross : 5/25/1999 mgross : 5/18/1999 terry : 5/14/1999 jenny : 7/1/1997 terry : 6/25/1997 terry : 6/24/1997 terry : 5/24/1996 mark : 3/18/1996 dateCreated Mon, 18 Mar 1996 03:00:00 EST creationDate Alan F. Scott : 3/18/1996 epochUpdated 1339743600 dateUpdated Fri, 15 Jun 2012 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(98)04474-2 publisherName Elsevier Science title Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. mimNumber 601130 referenceNumber 1 publisherAbbreviation ES pubmedID 10073515 source Lancet 353: 717-719, 1999. authors Aithal, G. P., Day, C. P., Kesteven, P. J. L., Daly, A. K. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0960-314X&volume=10&issue=6&spage=511 publisherName Lippincott Williams & Wilkins title Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. mimNumber 601130 referenceNumber 2 publisherAbbreviation LWW pubmedID 10975605 source Pharmacogenetics 10: 511-518, 2000. authors Aithal, G. P., Day, C. P., Leathart, J. B. S., Daly, A. K. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=14662709 publisherName HighWire Press title Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. mimNumber 601130 referenceNumber 3 publisherAbbreviation HighWire pubmedID 14662709 source Circulation 109: 178-183, 2004. authors Fichtlscherer, S., Dimmeler, S., Breuer, S., Busse, R., Zeiher, A. M., Fleming, I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.biomedcentral.com/1471-2164/4/9 publisherName BioMed Central title Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1. mimNumber 601130 referenceNumber 4 publisherAbbreviation BMC pubmedID 12697057 source BMC Genomics 4: 9, 2003. Note: Electronic Article. authors Gough, S. M., McDonald, M., Chen, X.-N., Korenberg, J. R., Neri, A., Kahn, T., Eccles, M. R., Morris, C. M. pubmedImages true publisherUrl http://www.biomedcentral.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(85)71149-4 publisherName Elsevier Science title A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. mimNumber 601130 referenceNumber 5 publisherAbbreviation ES pubmedID 8530044 source Genomics 28: 328-332, 1995. authors Gray, I. C., Nobile, C., Muresu, R., Ford, S., Spurr, N. K. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11926893 publisherName HighWire Press title Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. mimNumber 601130 referenceNumber 6 publisherAbbreviation HighWire pubmedID 11926893 source JAMA 287: 1690-1698, 2002. authors Higashi, M. K., Veenstra, D. L., Kondo, L. M., Wittkowsky, A. K., Srinouanprachanh, S. L., Farin, F. M., Rettie, A. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa0809329?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Estimation of the warfarin dose with clinical and pharmacogenetic data. mimNumber 601130 referenceNumber 7 publisherAbbreviation ATYPON pubmedID 19228618 source New Eng. J. Med. 360: 753-764, 2009. Note: Erratum: New Eng. J. Med. 361: 1613 only, 2009. authors {International Warfarin Pharmacogenetics Consortium} pubmedImages true publisherUrl http://www.atypon.com/ title Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. mimNumber 601130 referenceNumber 8 pubmedID 10208645 source Pharmacogenetics 9: 71-80, 1999. authors Kidd, R. S., Straughn, A. B., Meyer, M. C., Blaisdell, J., Goldstein, J. A., Dalton, J. T. pubmedImages false articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0960-314X&volume=14&issue=12&spage=813 publisherName Lippincott Williams & Wilkins title Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. mimNumber 601130 referenceNumber 9 publisherAbbreviation LWW pubmedID 15608560 source Pharmacogenetics 14: 813-822, 2004. authors King, B. P., Khan, T. I., Aithal, G. P., Kamali, F., Daly, A. K. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0960-314X&volume=13&issue=8&spage=473 publisherName Lippincott Williams & Wilkins title Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. mimNumber 601130 referenceNumber 10 publisherAbbreviation LWW pubmedID 12893985 source Pharmacogenetics 13: 473-480, 2003. authors Kirchheiner, J., Stormer, E., Meisel, C., Steinbach, N., Roots, I., Brockmoller, J. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961907 publisherName HighWire Press title A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. mimNumber 601130 referenceNumber 11 publisherAbbreviation HighWire pubmedID 10961907 source Blood 96: 1996-1998, 2000. authors Kohn, M. H., Pelz, H.-J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11588061 publisherName HighWire Press title Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. mimNumber 601130 referenceNumber 12 publisherAbbreviation HighWire pubmedID 11588061 source Blood 98: 2584-2587, 2001. authors Leung, A. Y. H., Chow, H. C. H., Kwong, Y. L., Lie, A. K. W., Fung, A. T. K., Chow, W. H., Yip, A. S. B., Liang, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16611750 publisherName HighWire Press title Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. mimNumber 601130 referenceNumber 13 publisherAbbreviation HighWire pubmedID 16611750 source J. Med. Genet. 43: 740-744, 2006. authors Li, T., Lange, L. A., Li, X., Susswein, L., Bryant, B., Malone, R., Lange, E. M., Huang, T.-Y., Stafford, D. W., Evans, J. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1744-6872&volume=16&issue=7&spage=497 publisherName Lippincott Williams & Wilkins title Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese. mimNumber 601130 referenceNumber 14 publisherAbbreviation LWW pubmedID 16788382 source Pharmacogenet. Genomics 16: 497-514, 2006. authors Maekawa, K., Fukushima-Uesaka, H., Tohkin, M., Hasegawa, R., Kajio, H., Kuzuya, N., Yasuda, K., Kawamoto, M., Kamatani, N., Suzuki, K., Yanagawa, T., Saito, Y., Sawada, J. pubmedImages false publisherUrl http://www.lww.com/ title Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. mimNumber 601130 referenceNumber 15 pubmedID 20555338 source J. Hum. Genet. 55: 582-589, 2010. authors Ross, K. A., Bigham, A. W., Edwards, M., Gozdzik, A., Suarez-Kurtz, G., Parra, E. J. pubmedImages false articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1098-3600&volume=7&issue=2&spage=97 publisherName Lippincott Williams & Wilkins title CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. mimNumber 601130 referenceNumber 16 publisherAbbreviation LWW pubmedID 15714076 source Genet. Med. 7: 97-104, 2005. authors Sanderson, S., Emery, J., Higgins, J. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://dx.doi.org/10.1038/tpj.2009.10 publisherName Nature Publishing Group title Global variation in CYP2C8-CYP2C9 functional haplotypes. mimNumber 601130 referenceNumber 17 publisherAbbreviation NPG pubmedID 19381162 source Pharmacogenomics J. 9: 283-290, 2009. authors Speed, W. C., Kang, S. P., Tuck, D. P., Harris, L. N., Kidd, K. K. pubmedImages true publisherUrl http://www.nature.com title Genetic association between sensitivity to warfarin and expression of CYP2C9*3. mimNumber 601130 referenceNumber 18 pubmedID 9352571 source Pharmacogenetics 7: 361-367, 1997. authors Steward, D. J., Haining, R. L., Henne, K. R., Davis, G., Rushmore, T. H., Trager, w. F., Rettie, A. E. pubmedImages false source Pharacogenetics 6: 341-349, 1996. mimNumber 601130 authors Sullivan-Klose, T. H., Ghanayem, B. I., Bell, D. A., Zhang, Z.-Y., Kaminsky, L. S., Shenfield, G. M., Miners, J. O., Birkett, D. J., Goldstein, J. A. title The role of the CYP2C9-leu-359 allelic variant in the tolbutamide polymorphism. referenceNumber 19 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15805193 publisherName HighWire Press title Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. mimNumber 601130 referenceNumber 20 publisherAbbreviation HighWire pubmedID 15805193 source Proc. Nat. Acad. Sci. 102: 5507-5512, 2005. authors Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(00)99016-0 publisherName Elsevier Science title Gene expression in distinct regions of the heart. mimNumber 601130 referenceNumber 21 publisherAbbreviation ES pubmedID 10768437 source Lancet 355: 979-983, 2000. authors Thum, T., Borlak, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nature01862 publisherName Nature Publishing Group title Crystal structure of human cytochrome P450 2C9 with bound warfarin. mimNumber 601130 referenceNumber 22 publisherAbbreviation NPG pubmedID 12861225 source Nature 424: 464-468, 2003. authors Williams, P. A., Cosme, J., Ward, A., Angove, H. C., Vinkovic, D. M., Jhoti, H. pubmedImages false publisherUrl http://www.nature.com source New Eng. J. Med. 344: 1393-1396, 2001. mimNumber 601130 authors Wood, A. J. J. title Racial differences in the response to drugs--pointers to genetic differences. (Letter) referenceNumber 23 articleUrl http://arjournals.annualreviews.org/doi/full/10.1146/annurev.pharmtox.41.1.815?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Molecular basis of ethnic differences in drug disposition and response. mimNumber 601130 referenceNumber 24 publisherAbbreviation ATYPON pubmedID 11264478 source Ann. Rev. Pharm. Toxicol. 41: 815-850, 2001. authors Xie, H.-G., Kim, R. B., Wood, A. J. J., Stein, C. M. pubmedImages false publisherUrl http://www.atypon.com/ externalLinks mgiIDs MGI:1919553,MGI:1917138 mgiHumanDisease false ncbiReferenceSequences 530393163,189242609 refSeqAccessionIDs NG_008385.1 dermAtlas false hprdIDs 03084 swissProtIDs P11712 umlsIDs C1332829 uniGenes Hs.282624 gtr true cmgGene false ensemblIDs ENSG00000138109,ENST00000260682 genbankNucleotideSequences 115529026,511803465,511803466,18088863,16751347,32891802,59042453,181363,258514,51038296,74230046,47682789,2618613,181361,181302,143805988,194391105,181365,181301,158259862,291613,148170318,148170319,291610 geneTests true approvedGeneSymbols CYP2C9 geneIDs 1559 proteinSequences 115529027,119570404,119570405,5705937,4239655,4239656,32891803,219571,181362,47682790,59042454,51038297,194391106,18088864,181366,181364,158259863,6686268,13699818,578818973 nextGxDx true locusSpecificDBs http://www.cypalleles.ki.se/;;Human Cytochrome P450 (CYP) Allele Nomenclature Committee

entryList

entry status live allelicVariantExists true epochCreated 921484800 geneMap geneSymbols BCS1L, FLNMS, GRACILE, BJS, PTD, MC3DN1 sequenceID 2299 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 603647 phenotypeInheritance Autosomal recessive phenotype Bjornstad syndrome phenotypeMimNumber 262000 phenotypeMappingKey 3 mimNumber 603647 phenotypeInheritance None phenotype GRACILE syndrome phenotypeMimNumber 603358 phenotypeMappingKey 3 mimNumber 603647 phenotypeInheritance Mitochondrial; Autosomal recessive phenotype Leigh syndrome phenotypeMimNumber 256000 phenotypeMappingKey 3 mimNumber 603647 phenotypeInheritance Autosomal recessive phenotype Mitochondrial complex III deficiency, nuclear type 1 phenotypeMimNumber 124000 chromosomeLocationStart 219524378 chromosomeSort 801 chromosomeSymbol 2 mimNumber 603647 geneInheritance None confidence C mappingMethod REc, Fd, LD geneName bcs1, S. cerevisiae, homolog-like mouseMgiID MGI:1914071 mouseGeneSymbol Bcs1l computedCytoLocation 2q35 cytoLocation 2q33 transcript uc002viq.3 chromosomeLocationEnd 219528165 chromosome 2 contributors Cassandra L. Kniffin - updated : 3/4/2014 Cassandra L. Kniffin - updated : 6/1/2010 Cassandra L. Kniffin - updated : 3/9/2010 Cassandra L. Kniffin - updated : 11/4/2009 Victor A. McKusick - updated : 3/21/2007 Victor A. McKusick - updated : 2/27/2007 Cassandra L. Kniffin - updated : 10/5/2005 Victor A. McKusick - updated : 10/29/2002 Ada Hamosh - updated : 8/22/2001 clinicalSynopsisExists false mimNumber 603647 allelicVariantList allelicVariant status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908571 text In 2 affected sibs and 1 fetus in a consanguineous family with mitochondrial complex III deficiency nuclear type 1 (MC3DN1; {124000}) characterized by neonatal tubulopathy, encephalopathy, and liver failure, {3:de Lonlay et al. (2001)} identified a homozygous 830G-A transition in the BCS1L gene, resulting in a ser277-to-asp (S277N) substitution. mutations BCS1L, SER277ASN number 1 clinvarAccessions RCV000006538;;1 status live name LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX III DEFICIENCY dbSnps rs121908572 text In 2 patients with complex III deficiency (MC3DN1; {124000}), a boy and a girl, born to unrelated consanguineous families, {3:de Lonlay et al. (2001)} identified the same homozygous C-to-T transition at nucleotide 296 in exon 1 of the BCS1L gene, causing the substitution of a leucine for a highly conserved proline at codon 99 (P99L). The patients had metabolic acidosis, hepatic involvement, neurologic deterioration, and brainstem and basal ganglia lesions consistent with a diagnosis of Leigh syndrome ({256000}). One patient had abnormal ventilation patterns and proximal renal tubulopathy. mutations BCS1L, PRO99LEU number 2 clinvarAccessions RCV000006539;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908573 text In a boy of Turkish origin with complex III deficiency (MC3DN1; {124000}) born to nonconsanguineous parents, {3:de Lonlay et al. (2001)} identified compound heterozygosity for 2 mutations in the BCS1L gene: a 464C-G transversion in exon 3 of the BCS1L gene, resulting in an arg155-to-pro (R155P) substitution, and a 1057G-A transition in exon 7, resulting in a val353-to-met (V353M; {603647.0004}) substitution. mutations BCS1L, ARG155PRO number 3 clinvarAccessions RCV000006540;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908574 text See {603647.0003} and {3:de Lonlay et al. (2001)}. mutations BCS1L, VAL353MET number 4 clinvarAccessions RCV000006541;;1 status live name GRACILE SYNDROME dbSnps rs28937590 text {13:Visapaa et al. (2002)} reported that all GRACILE syndrome ({603358}) patients in Finland were homozygous for a 232A-G mutation in exon 2 of the BCS1L gene, resulting in a ser78-to-gly (S78G) substitution. Unlike the Turkish patients reported by {3:de Lonlay et al. (2001)}, the Finnish patients had normal complex III activity and no neurologic problems, but did have marked iron overload. mutations BCS1L, SER78GLY number 5 clinvarAccessions RCV000006542;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908575 text In 2 Spanish sibs with fatal infantile complex III deficiency (MC3DN1; {124000}), {4:De Meirleir et al. (2003)} identified compound heterozygosity for mutation in the BCS1L gene: a 246C-T transition in exon 1, resulting in an arg45-to-cys (R45C) substitution, and a 279C-T transition in exon 1, resulting in an arg56-to-ter (R56X; {603647.0007}) substitution. The R45C substitution occurs in a crucial targeting signal of the gene and is predicted to interfere with proper protein functioning. Each parent was heterozygous for 1 of the mutations. Both patients had severe metabolic acidosis noted shortly after birth, as well as severe liver dysfunction and a renal tubulopathy. One died at age 3 weeks of lactic acidosis. The second infant also had obvious neurologic involvement, with delayed myelination, axial hypotonia, and developmental delay. He died at age 3 months. Postmortem liver examination of both infants showed liver fibrosis, severe cholestasis, and hepatosiderosis with accumulation of iron in aggregates of macrophages and in Kupffer cells. Mitochondria appeared enlarged with few or no cristae and a fluffy matrix. {4:De Meirleir et al. (2003)} suggested that the iron accumulation could be explained by the lack of incorporation of iron in the iron-sulfur cluster of complex III. {10:Ramos-Arroyo et al. (2009)} reported another Spanish infant with the R45C and R56X mutations. She presented with neonatal severe hypotonia, food intolerance, and vomiting. She soon developed a proximal renal tubulopathy with glucosuria, phosphaturia, and aminoaciduria, metabolic lactic acidosis, and hepatic involvement. Bilateral cataracts were also noted. At age 4 months, she showed nystagmus, hypertonia, microcephaly, developmental delay, and failure to thrive. Her neurologic condition and metabolic acidosis worsened rapidly, and she died at 6 months of age. Biochemical studies of muscle tissue showed impaired activity of mitochondrial complex III. {10:Ramos-Arroyo et al. (2009)} noted that this child did not have evidence of altered iron metabolism, as had been observed in the patients reported by {4:De Meirleir et al. (2003)}, and as has been observed in patients with the allelic disorder GRACILE syndrome ({603358}). {10:Ramos-Arroyo et al. (2009)} postulated that phenotypic variability even in individuals with the same BCS1L genotype may reflect tissue-specific expression of the mutant gene. mutations BCS1L, ARG45CYS number 6 clinvarAccessions RCV000006543;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908576 text See {603647.0006} and {4:De Meirleir et al. (2003)}. mutations BCS1L, ARG56TER number 7 clinvarAccessions RCV000006544;;1 status live name BJORNSTAD SYNDROME dbSnps rs121908577 text In affected members of the family with Bjornstad syndrome (BJS; {262000}) in which {7:Lubianca Neto et al. (1998)} demonstrated linkage to 2q, {6:Hinson et al. (2007)} identified homozygosity for a C-to-T transition in the BCS1L gene, resulting in an arg183-to-his (R183H) substitution. Eight individuals in 2 sibships related as first cousins once removed were affected; the parents in each case were consanguineous. mutations BCS1L, ARG183HIS number 8 clinvarAccessions RCV000006545;;1 status live name BJORNSTAD SYNDROME WITH MILD MITOCHONDRIAL COMPLEX III DEFICIENCY dbSnps rs121908578 text In a sporadic case of Bjornstad syndrome (BJS; {262000}) with mild mitochondrial complex III deficiency (MC3DN1; {124000}), {6:Hinson et al. (2007)} found compound heterozygosity for 2 missense mutations in the BCS1L gene: arg184 to cys (R184C) and gly35 to arg (G35R; {603647.0010}). In a Moroccan girl with mitochondrial complex III deficiency ({124000}), {5:Fernandez-Vizarra et al. (2007)} identified compound heterozygosity for the R184C mutation and a 547C-T transition in exon 3 of the BCS1L gene, resulting in an arg183-to-cys (R183C; {603647.0012}) substitution. She presented at age 9 months with acute psychomotor regression, hypotonia, and failure to thrive, which progressed to spastic quadriparesis and mental retardation associated with abnormal signal intensities in the thalami, basal ganglia, and periventricular white matter, consistent with an encephalopathy. Heart, liver, and kidneys were apparently unaffected, but she was also noted to have brittle hair. Studies in yeast showed that both mutations significantly reduced mitochondrial cytochrome content and respiratory activity, as well as caused a decreased incorporation of the Rieske iron-sulfur protein (UQCRFS1; {191327}) into complex III. Further studies showed decreased levels of fully assembled complex III. The findings suggested that BCS1L is necessary for proper complex III assembly. mutations BCS1L, ARG184CYS number 9 alternativeNames MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1, INCLUDED clinvarAccessions RCV000034811;;1;;;RCV000006546;;1 status live name BJORNSTAD SYNDROME WITH MILD MITOCHONDRIAL COMPLEX III DEFICIENCY dbSnps rs121908579 text See {603647.0009} and {6:Hinson et al. (2007)}. mutations BCS1L, GLY35ARG number 10 clinvarAccessions RCV000006548;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs121908580 text In a 4-year-old Spanish boy with isolated mitochondrial complex III deficiency (MC3DN1; {124000}), {1:Blazquez et al. (2009)} identified a homozygous 148A-G transition in exon 1 of the BCS1L gene, resulting in a thr50-to-ala (T50A) substitution in the mitochondrial sorting sequence. He presented at 6 months of age with psychomotor retardation, failure to thrive, hypotonia, lactic acidosis, and hepatic dysfunction. Physical examination showed unstable head support, poor eye fixation, coarse facies, and epicanthus. There was hypertrichosis of the frontal head zone and limbs, and excessive fat distribution in the upper back, neck, hands and feet, with almost no fat on the limbs. Respiratory chain activity in muscle and fibroblasts showed an isolated complex III defect (58% of normal in muscle, 93% in fibroblasts). At age 4 years, he still showed psychomotor retardation, had developed mild sensorineural hearing loss, and persistent lactic acidemia, but renal function, hair, and iron metabolism were normal. Brain MRI was normal. The mutation was not found in 400 control alleles, and each unaffected parent was heterozygous for the mutation. mutations BCS1L, THR50ALA number 11 clinvarAccessions RCV000006549;;1 status live name MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 1 dbSnps rs144885874 text See {603647.0009} and {5:Fernandez-Vizarra et al. (2007)}. mutations BCS1L, ARG183CYS number 12 clinvarAccessions RCV000006550;;1 status live name BJORNSTAD SYNDROME dbSnps rs587777278 text In 5 members of a large Pakistani family with Bjornstad syndrome (BJS; {262000}), {11:Siddiqi et al. (2013)} identified a homozygous c.901T-A transversion in exon 8 of the BCS1L gene, resulting in a tyr301-to-asn (Y301N) substitution in the AAA domain. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. It was not found in 137 control individuals or in the 1000 Genomes Project database. The mutation was predicted to change the binding affinity of the AAA domain for other molecules, but functional studies were not performed. mutations BCS1L, TYR301ASN number 13 clinvarAccessions RCV000114392;;1 prefix * titles preferredTitle BCS1, S. CEREVISIAE, HOMOLOG-LIKE; BCS1L textSectionList textSection textSectionTitle Description textSectionContent The human BCS1L gene encodes a homolog of S. cerevisiae bcs1 protein involved in the assembly of complex III of the mitochondrial respiratory chain. textSectionName description textSectionTitle Cloning textSectionContent The S. cerevisiae bcs1 protein is a constituent of the inner mitochondrial membrane and is required for the expression of functional ubiquinol-cytochrome-c reductase (bc1) complex (see {191328}). The bcs1 protein shares sequence similarity with members of the AAA (ATPases associated with various cellular activities) superfamily (see {601681}). By searching an EST database for sequences related to bcs1, {9:Petruzzella et al. (1998)} identified a cDNA encoding human BCS1L (BCS1-like). The predicted 420-amino acid human protein is 50% identical to yeast bcs1 and, like bcs1, contains 2 conserved nucleotide-binding motifs. Although BCS1L does not contain an N-terminal mitochondrial targeting sequence, in vitro mitochondrial import and trypsin-protection assays demonstrated that it is imported into mitochondria. Northern blot analysis revealed that BCS1L is expressed ubiquitously as a 1.4-kb mRNA. The authors also detected a 4.5-kb transcript that they considered to be either an alternative BCS1L mRNA or an mRNA derived from a related gene. textSectionName cloning textSectionTitle Gene Function textSectionContent Found within the inner mitochondrial membrane, BCS1L is presumed to facilitate insertion of Rieske Fe/S protein into precursors to complex III during assembly of the respiratory chain ({2:Cruciat et al., 1999}). Complex III then becomes assembled with complexes IV and I into a respirasome supercomplex that facilitates the electron transfer required for the synthesis of ATP. textSectionName geneFunction textSectionTitle Mapping textSectionContent Based on sequence similarity to ESTs, {9:Petruzzella et al. (1998)} tentatively mapped the BCS1L gene to 2q33. textSectionName mapping textSectionTitle Gene Structure textSectionContent {3:De Lonlay et al. (2001)} showed that the BCS1L gene consists of 7 exons. textSectionName geneStructure textSectionTitle Molecular Genetics textSectionContent Mitochondrial Complex III Deficiency, Nuclear Type 1 {3:De Lonlay et al. (2001)} found 4 biallelic mutations in the BCS1L gene in 6 patients from 4 families with mitochondrial complex III deficiency nuclear type 1 (MC3DN1; {124000}) characterized by neonatal proximal tubulopathy, hepatic involvement, and encephalopathy. Complementation studies in yeast confirmed the deleterious effect of these missense mutations. {3:De Lonlay et al. (2001)} suggested that mutation of BCS1L is a frequent cause of complex III deficiency, as one-third of their Turkish patients had mutations in the BSC1L gene. {3:De Lonlay et al. (2001)} reported that they had not been able to detect BCS1L mutations in complex III-deficient patients with clinical presentations other than neonatal tubulopathy with hepatic involvement and encephalopathy. GRACILE Syndrome The GRACILE (growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death) syndrome ({603358}) belongs to the disease heritage of Finland. All affected families carry the same ancestral haplotype on 2q33-q37, indicating 1 founder mutation ({12:Visapaa et al., 1998}). {13:Visapaa et al. (2002)} identified a homozygous ser78-to-gly mutation (S78G; {603358.0005}) in the BCS1L gene in all Finnish patients with GRACILE syndrome studied. In addition, they identified 5 different mutations in the BCS1L gene in 3 British infants, previously reported by {8:Morris et al. (1995)}, whose symptoms resembled those in GRACILE syndrome but who also had complex III deficiency and neurologic symptoms. The phenotype of the Turkish patients in whom {3:de Lonlay et al. (2001)} demonstrated mutations in the BCS1L gene was distinctly different from that of the Finnish patients. Whereas the Turkish patients had complex III deficiency, the Finnish patients had complex III activity within the normal range. The Finnish patients had no neurologic problems, but had marked hepatic iron overload, associated with abnormal levels of proteins involved in iron transfer and storage, and free plasma iron. These findings implied that BCS1L has another cellular function that is uncharacterized but essential, and that it is putatively involved in iron metabolism. Bjornstad Syndrome Bjornstad syndrome ({262000}) is an autosomal recessive condition characterized by sensorineural hearing loss and pili torti. {7:Lubianca Neto et al. (1998)} mapped the Bjornstad syndrome locus to 2q34-q36. {6:Hinson et al. (2007)} refined the map location of the disorder to 2q35 and demonstrated mutations in the BCS1L gene (e.g., {603647.0008}). In 5 members of a large Pakistani family with Bjornstad syndrome, {11:Siddiqi et al. (2013)} identified a homozygous missense mutation in the BCS1L gene (Y301N; {603647.0013}). textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent To understand how BCS2L mutations cause such widely different clinical phenotypes, {6:Hinson et al. (2007)} considered the locations of defects on the BCS1L protein structure and compared the function of mutant BCS1L in yeast and in human lymphocytes. Their studies showed that all BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit of respiration in human mitochondria), but the clinical severity of the mutations was correlated with the production of reactive oxygen species. The data indicated that in addition to mitochondrial heteroplasmy and variable energy requirements of tissues, tissue-specific sensitivities to reactive oxygen species contribute to the variability of the manifestations of mitochondrial defects. textSectionName genotypePhenotypeCorrelations geneMapExists true editHistory alopez : 04/08/2014 mcolton : 3/7/2014 ckniffin : 3/4/2014 carol : 4/8/2013 ckniffin : 4/8/2013 wwang : 6/4/2010 ckniffin : 6/1/2010 wwang : 3/24/2010 ckniffin : 3/9/2010 wwang : 11/20/2009 wwang : 11/18/2009 ckniffin : 11/4/2009 carol : 3/21/2007 carol : 3/21/2007 terry : 2/27/2007 wwang : 10/12/2005 ckniffin : 10/5/2005 carol : 9/21/2005 ckniffin : 8/29/2005 terry : 4/21/2005 terry : 3/3/2005 carol : 7/10/2003 ckniffin : 7/9/2003 carol : 11/1/2002 tkritzer : 10/30/2002 terry : 10/29/2002 alopez : 9/4/2001 terry : 8/22/2001 alopez : 3/15/1999 alopez : 3/15/1999 dateCreated Mon, 15 Mar 1999 03:00:00 EST creationDate Rebekah S. Rasooly : 3/15/1999 epochUpdated 1396940400 dateUpdated Tue, 08 Apr 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0960-8966(08)00715-3 publisherName Elsevier Science title Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient. mimNumber 603647 referenceNumber 1 publisherAbbreviation ES pubmedID 19162478 source Neuromusc. Disord. 19: 143-146, 2009. authors Blazquez, A., Gil-Borlado, M. C., Moran, M., Verdu, A., Cazorla-Calleja, M. R., Martin, M. A., Arenas, J., Ugalde, C. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1093/emboj/18.19.5226 publisherName Nature Publishing Group title Bsc1p, an AAA-family member, is a chaperone for the assembly of the cytochrome bc(1) complex. mimNumber 603647 referenceNumber 2 publisherAbbreviation NPG pubmedID 10508156 source EMBO J. 18: 5226-5233, 1999. authors Cruciat, C. M., Hell, K., Folsch, H., Neupert, W., Stuart, R. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng706 publisherName Nature Publishing Group title A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. mimNumber 603647 referenceNumber 3 publisherAbbreviation NPG pubmedID 11528392 source Nature Genet. 29: 57-60, 2001. authors de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J.-W., Benayoun, E., Chretien, D., Kadhom, N., Lombes, A., Ogier de Baulny, H., Niaudet, P., Munnich, A., Rustin, P., Rotig, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.20171 publisherName John Wiley & Sons, Inc. title Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. mimNumber 603647 referenceNumber 4 publisherAbbreviation Wiley pubmedID 12910490 source Am. J. Med. Genet. 121A: 126-131, 2003. authors De Meirleir, L., Seneca, S., Damis, E., Sepulchre, B., Hoorens, A., Gerlo, E., Garcia Silva, M. T., Hernandez, E. M., Lissens, W., Van Coster, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17403714 publisherName HighWire Press title Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. mimNumber 603647 referenceNumber 5 publisherAbbreviation HighWire pubmedID 17403714 source Hum. Molec. Genet. 16: 1241-1252, 2007. authors Fernandez-Vizarra, E., Bugiani, M., Goffrini, P., Carrara, F., Farina, L., Procopio, E., Donati, A., Uziel, G., Ferrero, I., Zeviani, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa055262?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. mimNumber 603647 referenceNumber 6 publisherAbbreviation ATYPON pubmedID 17314340 source New Eng. J. Med. 356: 809-819, 2007. authors Hinson, J. T., Fantin, V. R., Schonberger, J., Breivik, N., Siem, G., McDonough, B., Sharma, P., Keogh, I., Godinho, R., Santos, F., Esparza, A., Nicolau, Y., Selvaag, E., Cohen, B. H., Hoppel, C. L., Tranebjaerg, L., Eavey, R. D., Seidman, J. G., Seidman, C. E. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61532-8 publisherName Elsevier Science title The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36. mimNumber 603647 referenceNumber 7 publisherAbbreviation ES pubmedID 9545407 source Am. J. Hum. Genet. 62: 1107-1112, 1998. authors Lubianca Neto, J. F., Lu, L., Eavey, R. D., Macias Flores, M. A., Martinez Caldera, R., Sangwatanaroj, S., Schott, J. J., McDonough, B., Santos, J. I., Seidman, C. E., Seidman, J. G. pubmedImages false publisherUrl http://www.elsevier.com/ title Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain. mimNumber 603647 referenceNumber 8 pubmedID 7577396 source Pediat. Nephrol. 9: 407-411, 1995. authors Morris, A. A. M., Taylor, R. W., Birch-Machin, M. A., Jackson, M. J., Coulthard, M. G., Bindoff, L. A., Welch, J. R., Howell, N., Turnbull, D. M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(98)95580-X publisherName Elsevier Science title Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain. mimNumber 603647 referenceNumber 9 publisherAbbreviation ES pubmedID 9878253 source Genomics 54: 494-504, 1998. authors Petruzzella, V., Tiranti, V., Fernandez, P., Ianna, P., Carrozzo, R., Zeviani, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2009&volume=75&issue=6&spage=585 publisherName Blackwell Publishing title Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. (Letter) mimNumber 603647 referenceNumber 10 publisherAbbreviation Blackwell pubmedID 19508421 source Clin. Genet. 75: 585-587, 2009. authors Ramos-Arroyo, M. A., Hualde, J., Ayechu, A., De Meirleir, L., Seneca, S., Nadal, N., Briones, P. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome. mimNumber 603647 referenceNumber 11 pubmedID 24172246 source J. Hum. Genet. 58: 819-821, 2013. authors Siddiqi, S., Siddiq, S., Mansoor, A., Oostrik, J., Ahmad, N., Kazmi, S. A. R., Kremer, H., Qamar, R., Schraders, M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/ publisherName Elsevier Science title Assignment of the locus for a new lethal neonatal metabolic syndrome to 2q33-37. mimNumber 603647 referenceNumber 12 publisherAbbreviation ES pubmedID 9792866 source Am. J. Hum. Genet. 63: 1396-1403, 1998. authors Visapaa, I., Fellman, V., Varilo, T., Palotie, A., Raivio, K. O., Peltonen, L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60371-1 publisherName Elsevier Science title GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. mimNumber 603647 referenceNumber 13 publisherAbbreviation ES pubmedID 12215968 source Am. J. Hum. Genet. 71: 863-876, 2002. authors Visapaa, I., Fellman, V., Vesa, J., Dasvarma, A., Hutton, J. L., Kumar, V., Payne, G. S., Makarow, M., Van Coster, R., Taylor, R. W., Turnbull, D. M., Suomalainen, A., Peltonen, L. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks flybaseIDs FBgn0032195 mgiIDs MGI:1914071 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 383087735,383087729,383087731,530370741,530370743,119964731,530370739,119964729 refSeqAccessionIDs NG_033099.1,NG_008018.1 dermAtlas false hprdIDs 04708 swissProtIDs Q9Y276 zfinIDs ZDB-GENE-040426-938 uniGenes Hs.471401 gtr true cmgGene false ensemblIDs ENSG00000074582,ENST00000359273 umlsIDs C1412777 genbankNucleotideSequences 2795915,13540331,42517295,33096766,511859080,158259748,81179068,80529862,123996776,71517966,22750484,3599961,157154546,62898767,33875412,21755642,190691820,18450223,190690442,33873660,123981947,148168302 geneTests true approvedGeneSymbols BCS1L geneIDs 617 proteinSequences 33096767,158259749,123996777,22750485,4757852,190690443,578804710,119964730,123981948,119591040,119591041,383087732,13540332,119591042,119591043,13960118,62988645,119591044,46397351,530370744,119591045,119591046,2795916,383087730,530370740,530370742,3599962,383087736,12653295,157154547,62898768,190691821,193788337 geneticsHomeReferenceIDs gene;;BCS1L;;BCS1L

entryList

entry status live allelicVariantExists true epochCreated 518079600 geneMap geneSymbols MYH7, CMH1, MPD1, CMD1S, SPMM, SPMD sequenceID 9918 phenotypeMapList phenotypeMap phenotypeMimNumber 613426 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 604169,115200 phenotypeMappingKey 3 phenotype Cardiomyopathy, dilated, 1S phenotypeMimNumber 192600 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 192600 phenotypeMappingKey 3 phenotype Cardiomyopathy, familial hypertrophic, 1 phenotypeMappingKey 3 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotype Laing distal myopathy phenotypeMimNumber 160500 phenotypeMimNumber 613426 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 604169,115200 phenotypeMappingKey 3 phenotype Left ventricular noncompaction 5 phenotypeMappingKey 3 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotype Myopathy, myosin storage phenotypeMimNumber 608358 phenotypeMappingKey 3 mimNumber 160760 phenotypeInheritance Autosomal dominant phenotype Scapuloperoneal syndrome, myopathic type phenotypeMimNumber 181430 chromosomeLocationStart 23881946 chromosomeSort 75 chromosomeSymbol 14 mimNumber 160760 confidence C mappingMethod REa, RE, D, A geneName Myosin, heavy polypeptide-7, cardiac muscle, beta comments 5'-B-4.5kb-A-3' geneInheritance None computedCytoLocation 14q11.2 cytoLocation 14q12 transcript uc001wjx.3 chromosomeLocationEnd 23904869 chromosome 14 contributors Ada Hamosh - updated : 04/28/2014 Ada Hamosh - updated : 1/29/2014 Marla J. F. O'Neill - updated : 10/9/2013 Marla J. F. O'Neill - updated : 9/4/2013 Cassandra L. Kniffin - updated : 5/3/2012 Marla J. F. O'Neill - updated : 4/7/2011 Cassandra L. Kniffin - updated : 10/26/2010 Patricia A. Hartz - updated : 10/6/2010 Ada Hamosh - updated : 9/27/2010 Marla J. F. O'Neill - updated : 8/5/2010 Marla J. F. O'Neill - updated : 6/7/2010 Cassandra L. Kniffin - updated : 10/14/2009 Victor A. McKusick - updated : 2/19/2008 Cassandra L. Kniffin - updated : 1/7/2008 Marla J. F. O'Neill - updated : 12/4/2007 Marla J. F. O'Neill - updated : 11/21/2007 Ada Hamosh - updated : 6/4/2007 Cassandra L. Kniffin - updated : 5/31/2006 Marla J. F. O'Neill - updated : 2/23/2006 Carol A. Bocchini - updated : 8/12/2005 Marla J. F. O'Neill - updated : 7/13/2005 Cassandra L. Kniffin - updated : 6/27/2005 Cassandra L. Kniffin - updated : 6/9/2005 Victor A. McKusick - updated : 4/11/2005 Cassandra L. Kniffin - updated : 1/25/2005 Victor A. McKusick - updated : 9/9/2004 Victor A. McKusick - updated : 1/15/2004 Cassandra L. Kniffin - updated : 12/24/2003 Victor A. McKusick - updated : 5/9/2003 Victor A. McKusick - updated : 3/7/2003 Victor A. McKusick - updated : 11/5/2002 Michael J. Wright - updated : 8/2/2002 Stylianos E. Antonarakis - updated : 12/17/2001 Victor A. McKusick - updated : 1/4/2001 Victor A. McKusick - updated : 1/19/2000 Victor A. McKusick - updated : 11/15/1999 Victor A. McKusick - updated : 5/18/1998 Clair A. Francomano - updated : 5/7/1998 externalLinks cmgGene false mgiHumanDisease false hprdIDs 01175 nbkIDs NBK1259;;Congenital Fiber-Type Disproportion;;;NBK1433;;Laing Distal Myopathy;;;NBK1768;;Hypertrophic Cardiomyopathy Overview refSeqAccessionIDs NG_007884.1 uniGenes Hs.719946 approvedGeneSymbols MYH7 nextGxDx true locusSpecificDBs http://genepath.med.harvard.edu/~seidman/cg3/genes/MYH7_info.html;;Sarcomere Protein Gene Mutation Database;;;http://www.angis.org.au/Databases/Heart/heartbreak.html;;FHC Mutation Database flybaseIDs FBgn0264695 dermAtlas false umlsIDs C1417542 gtr true geneIDs 4625 swissProtIDs P12883 zfinIDs ZDB-GENE-991123-5 ensemblIDs ENSG00000092054,ENST00000355349 geneTests true ncbiReferenceSequences 530403849,530403848,115496168,530403846 genbankNucleotideSequences 188992,188996,148130843,48476972,12053671,62088995,189008,34643,13897280,24429600,12185325,82161776,511796503,34841,29467,164692557,124302197,29726,34847,49504466,189028,34859,81022911,34860,85567607,179511,148342498,74230042,85567023,179509,201067588,188985 proteinSequences 115496169,48476973,1617111,825694,81022912,34644,4379031,62088996,530403850,386973,530403847,119586555,119586556,29468,119586557,124302198,386970,29727,12053672,85567608,83304912,85567024,148342499,179510,553597,601916,179508,188986,201067589 geneticsHomeReferenceIDs gene;;MYH7;;MYH7 clinicalSynopsisExists false mimNumber 160760 allelicVariantList allelicVariant status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913624 text In the large French-Canadian kindred originally reported by {58:Pare et al. (1961)} and shown to have linkage of the cardiac disorder ({192600}) to markers on the proximal portion of 14q, {24:Geisterfer-Lowrance et al. (1990)} found a missense mutation in the beta cardiac myosin heavy chain that converted arginine-403 to glutamine (R403Q). A guanine residue at position 10,162 (enumerated as in {33:Jaenicke et al., 1990}) was mutated to an adenine residue. The mutation generated a new DdeI site and changed the CGG(arg) codon to CAG(gln). {60:Perryman et al. (1992)} found that the R403Q mutation was identifiable in myocardial mRNA. {65:Ross and Knowlton (1992)} reviewed this discovery beginning with the patients first seen by Pare in the 1950s. Using an isolated, isovolumic heart preparation where cardiac performance was measured simultaneously with cardiac energetics using (31)P nuclear magnetic resonance spectroscopy, {69:Spindler et al. (1998)} studied the effects of the codon 403 missense mutation. They observed 3 major alterations in the physiology and bioenergetics of the mutant mouse hearts. First, while there was no evidence for systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions the mutant R403Q mouse hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, mutant hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wildtypes. The authors concluded that the hearts from mice carrying the R403Q mutation have workload-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggested that an energy-requiring process may contribute to the observed diastolic dysfunction. {5:Bashyam et al. (2003)} pointed out that polymorphism in the ACE1 gene ({106180}) had been shown to affect the prognosis in familial hypertrophic cardiomyopathy. The DD allele of the ACE1 gene ({106180.0001}) was associated with a severe form of hypertrophy and sudden death in patients with familial hypertrophic cardiomyopathy ({32:Iwai et al., 1994}). {73:Tesson et al. (1997)} established an association of the D allele at the ACE1 locus with the R403Q mutation in MYH7, but not with MYBPC3 ({600958}) mutations. mutations MYH7, ARG403GLN number 1 clinvarAccessions RCV000015143;;1;;;RCV000035708;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs3218713 text Using a ribonuclease protection assay, {78:Watkins et al. (1992)} screened the beta cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy ({192600}). Seven different mutations were identified in 12 of the 25 families; see {160760.0003}-{160760.0007}. All were missense mutations; 5 were clustered in the head of the beta-chain, which comprises the 5-prime 866 amino acids, and 2 were located in the 5-prime or hinge portion of the rod part. Six of the mutations resulted in a change in the charge of the amino acid. These patients had a shorter life expectancy (mean age at death, 33 years) than did patients with the one mutation that did not produce a change in charge, val606-to-met. One of the mutations they found was a substitution of glutamine for arginine-249. mutations MYH7, ARG249GLN number 2 clinvarAccessions RCV000015144;;1;;;RCV000036000;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913625 text See {160760.0002}. {78:Watkins et al. (1992)} found substitution of cysteine for arginine-453 in 2 unrelated families with familial hypertrophic cardiomyopathy ({192600}). One of the families also had an alpha/beta cardiac myosin heavy chain hybrid gene which was presumably of no functional significance, inasmuch as the 5-prime promoter region was derived from the alpha subunit. In a 3-generation Chinese family, {40:Ko et al. (1996)} observed the coexistence of sudden death and end-stage heart failure due to the arg453-to-cys mutation. The average age of death in affected members of the family was 34 years. mutations MYH7, ARG453CYS number 3 clinvarAccessions RCV000015145;;1;;;RCV000035717;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913626 text See {160760.0002}. {78:Watkins et al. (1992)} found the gly584-to-arg mutation in 2 unrelated families with familial hypertrophic cardiomyopathy ({192600}). mutations MYH7, GLY584ARG number 4 clinvarAccessions RCV000035744;;1;;;RCV000015146;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913627 text See {160760.0002}. {78:Watkins et al. (1992)} found this mutation in 3 unrelated families with familial hypertrophic cardiomyopathy ({192600}). Of the 7 mutations they found, this was the only one that produced no change in the charge of the amino acid. Although the affected patients did not differ in other clinical manifestations of familial hypertrophic cardiomyopathy, patients in this family had nearly normal survival; mean age at death was 33 years in the 11 families with one or another mutation that substituted an amino acid with a different charge. {7:Blair et al. (2001)} identified the val606-to-met mutation in a family in which 2 individuals had suffered sudden death at an early age. The mutation was found to be in cis with an ala728-to-val (A728V) mutation ({160760.0025}). mutations MYH7, VAL606MET number 5 clinvarAccessions RCV000035750;;2;;;RCV000015147;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913628 text See {160760.0002}. {78:Watkins et al. (1992)} found this mutation in 1 family with familial hypertrophic cardiomyopathy ({192600}). The mutation was found in exon 23 by RNase protection assay. It occurred as a new mutation in a 44-year-old female; the parents lacked the mutation which, however, was transmitted to her 24-year-old daughter. mutations MYH7, GLU924LYS number 6 clinvarAccessions RCV000015148;;1;;;RCV000035824;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913629 text See {160760.0002}. {78:Watkins et al. (1992)} found this mutation in 1 family with familial hypertrophic cardiomyopathy ({192600}). mutations MYH7, GLU949LYS number 7 clinvarAccessions RCV000015149;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913630 text Among 7 individuals with sporadic hypertrophic cardiomyopathy ({192600}), {79:Watkins et al. (1992)} identified mutations in the beta cardiac MHC genes in 2. Since the parents were neither clinically nor genetically affected, the authors concluded that the mutations in each proband arose de novo. Transmission of the mutation and disease to an offspring occurred in 1 pedigree ({160760.0006}), predicting that these were germline mutations. One proband, a 40-year-old female, was shown by RNase protection assay to have a C-to-T transition in exon 20 at nucleotide 2253, leading to a change from arginine to cysteine at codon 723. Arginine residue 723 is conserved among all known cardiac MHCs and all vertebrate striated muscle MHCs except the human perinatal and rabbit skeletal isoforms; mutation of a cysteine residue constitutes a nonconservative substitution with a change in net charge. mutations MYH7, ARG723CYS number 8 clinvarAccessions RCV000035772;;2;;;RCV000015151;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 text In a family with several members affected with hypertrophic cardiomyopathy ({192600}), {47:Marian et al. (1992)} identified a novel 9.5-kb BamHI RFLP detected by an MYH7 probe on Southern blots of DNA from the proband. PCR was used to amplify the segment of the gene; sequence analysis showed a 2.4-kb deletion involving 1 allele. The deletion included part of intron 39, exon 40 including the 3-prime untranslated region and the polyadenylation signal, and part of the region between the beta and alpha myosin heavy chain genes. The deletion was inherited by 2 daughters of the proband and a grandson, aged 33, 32, and 10 years, respectively, who were, however, free of signs of the disorder. The 67-year-old proband had late onset of the disorder which was first diagnosed in him at the age of 59 when he presented with atypical chest pain, lightheadedness, and decreased exercise tolerance. On cardiac examination, he showed an S4 heart sound and a systolic ejection murmur. EKG showed left ventricular hypertrophy with repolarization abnormalities. Ventricular hypertrophy was demonstrated by echocardiogram which also showed systolic anterior motion of the anterior leaflet of the mitral valve. There was a 25-mm Hg left ventricular outflow tract gradient. From observations in C. elegans, it was predicted that an unstable mRNA might result from this mutation. mutations MYH7, 2.4-KB DEL number 9 clinvarAccessions RCV000015152;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913631 text {19:Fananapazir et al. (1993)} found evidence, on soleus muscle biopsy, of central core disease ({117000}) in 10 of 13 hypertrophic cardiomyopathy patients with the leu908-to-val mutation. Although the mutations in the MYH7 gene were associated with skeletal muscle changes characteristic of central core disease, such was not found in patients with hypertrophic cardiomyopathy unlinked to MYH7. Notably, in 1 branch of a family with the L908V mutation, 2 adults and 3 children had histologic changes of central core disease without evidence of cardiac hypertrophy by echocardiogram. One of the adults had skeletal myopathic changes. {50:McKenna (1993)}, who stated that he had never seen clinical evidence of skeletal myopathy in patients with CMH1 ({192600}), doubted the significance of the findings. mutations MYH7, LEU908VAL number 10 clinvarAccessions RCV000078452;;1;;;RCV000015153;;1;;;RCV000035820;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913632 text In 1 of 3 patients with hypertrophic cardiomyopathy ({192600}) and the G741R mutation, {19:Fananapazir et al. (1993)} found microscopic changes of central core disease on soleus muscle biopsy. mutations MYH7, GLY741ARG number 11 clinvarAccessions RCV000035779;;1;;;RCV000015154;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913633 text In 1 patient with the G256E mutation and familial hypertrophic cardiomyopathy ({192600}), {19:Fananapazir et al. (1993)} found histologic changes on soleus muscle biopsy consistent with central core disease. mutations MYH7, GLY256GLU number 12 clinvarAccessions RCV000015155;;1;;;RCV000036002;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913634 text Using PCR-DNA conformation polymorphism analysis, {26:Harada et al. (1993)} found an A-to-G transition at codon 778 leading to replacement of the asp residue by gly. The mutation was found in 5 unrelated Japanese patients and their affected family members with hypertrophic cardiomyopathy ({192600}). mutations MYH7, ASP778GLY number 13 clinvarAccessions RCV000015156;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913624 text In 2 French pedigrees with familial hypertrophic cardiomyopathy ({192600}), {15:Dausse et al. (1993)} performed linkage analysis using 2 microsatellite markers located in the MYH7 gene, as well as 4 highly informative markers that mapped to the 14q11-q12 region. Linkage to the markers was found in pedigree 720, but results were not conclusive for pedigree 730. Haplotype of 6 markers allowed identification of affected individuals and of some unaffected subjects who were carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing: arg403-to-leu and arg403-to-trp in families 720 and 730, respectively. The arg403-to-leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the arg403-to-trp mutation appeared to be less severe. Codon 403 of the MYH7 gene appears, therefore, to be a hotspot for mutations causing CMH. The first mutation identified in this disorder involved codon 403 ({160760.0001}). mutations MYH7, ARG403LEU number 14 clinvarAccessions RCV000015157;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs3218714 text See {160760.0014}. mutations MYH7, ARG403TRP number 15 clinvarAccessions RCV000035707;;1;;;RCV000015158;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913636 text In a family of Japanese ancestry in which a mild form of familial hypertrophic cardiomyopathy ({192600}) occurred, {1:Anan et al. (1994)} found a 1624T-G transversion in exon 15, resulting in a phe513-to-cys (F513C) substitution. The F513C mutation did not alter the charge of the encoded amino acid, which may be related to the finding of near-normal life expectancy in this family. In a Japanese proband with CMH (CMH17; {613873}), {49:Matsushita et al. (2007)} identified heterozygosity for a missense mutation in the JPH2 gene ({605267.0004}); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 heterozygous mutations in MYH7, F513C and A26V. Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and the MYH7 A26V mutation. The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. mutations MYH7, PHE513CYS number 16 clinvarAccessions RCV000015159;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913637 text In 4 unrelated families with hypertrophic cardiomyopathy ({192600}) with a high incidence of premature death and an average life expectancy in affected individuals of 38 years, {1:Anan et al. (1994)} found an R719W mutation in exon 19 changing the charge of the amino acid by -1. The difference in survival of individuals bearing the R719W mutation as compared with those with the F513C mutation ({160760.0016}) was demonstrated by Kaplan-Meier product-limit curves (their Figure 4). In a 6.5-year-old boy with a severe form of hypertrophic cardiomyopathy, {35:Jeschke et al. (1998)} identified 2 missense mutations: one was the R719W mutation and the other was an M349T mutation ({160760.0020}), which was inherited through the maternal grandmother. Six family members who were carriers of the M349T mutation were clinically unaffected. The authors hypothesized that compound heterozygosity for the R719W and M349T mutations resulted in the particularly severe phenotype of early onset. mutations MYH7, ARG719TRP number 17 clinvarAccessions RCV000015160;;1;;;RCV000035768;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913638 text In a small family from the U.K. in which 2 individuals affected by hypertrophic cardiomyopathy ({192600}) were alive, including one who had been resuscitated after sudden death at age 19, {1:Anan et al. (1994)} found a G-to-A transition at nucleotide 2232 resulting in a gly716-to-arg (G716R) substitution (charge change = +1) of the encoded amino acid. mutations MYH7, GLY716ARG number 18 clinvarAccessions RCV000035767;;1;;;RCV000015161;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913639 text In 2 brothers with hypertrophic cardiomyopathy ({192600}) who died in their thirties, {56:Nishi et al. (1994)} found a G-to-A transition in codon 935 of the MYH7 gene, leading to a replacement of glutamic acid with lysine. The brothers were homozygous, whereas the parents, who were first cousins, were heterozygous for the mutation and had cardiac hypertrophy without clinical symptoms. An elder sister was also heterozygous for the mutation but did not manifest cardiac hypertrophy. {56:Nishi et al. (1994)} suggested that there was a gene dosage effect on clinical manifestations in this family. mutations MYH7, GLU935LYS number 19 clinvarAccessions RCV000015162;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913640 text See {160760.0017} and {35:Jeschke et al. (1998)}. mutations MYH7, MET349THR number 20 clinvarAccessions RCV000015150;;1;;;RCV000127019;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913641 text In a study of mutations causing hypertrophic cardiomyopathy ({192600}) in 2 South African subpopulations, {53:Moolman-Smook et al. (1999)} identified an arg719-to-gln (R719Q) mutation in the MYH7 gene. The mutation occurred in a family of white ancestry and had previously been described by {78:Watkins et al. (1992)} in a Canadian family. The codon is the same as that involved in the arg719-to-trp mutation ({160760.0017}). mutations MYH7, ARG719GLN number 21 clinvarAccessions RCV000015163;;1;;;RCV000035770;;1 status live name CARDIOMYOPATHY, DILATED, 1S dbSnps rs121913642 text In a family with familial dilated cardiomyopathy-1S ({613426}), {37:Kamisago et al. (2000)} demonstrated a T-to-C change at nucleotide 1680 in exon 16 of the cardiac beta-myosin heavy chain gene, causing a ser532-to-pro missense mutation. An affected member of this family had received a cardiac transplant cardiac beta-myosin heavy chain gene. An affected member of this family had received a cardiac transplant at 23 years of age. A 20-year-old female suffered postpartum congestive heart failure and sudden death. A female child developed congestive heart failure at 2 years of age. mutations MYH7, SER532PRO number 22 clinvarAccessions RCV000015164;;1 status live name CARDIOMYOPATHY, DILATED, 1S dbSnps rs121913643 text In a family with familial dilated cardiomyopathy-1S ({613426}), {37:Kamisago et al. (2000)} found a C-to-G transversion at nucleotide 2378 in exon 21 of the cardiac beta-myosin heavy chain gene, causing a phe764-to-leu missense mutation. The 33-year-old father was given a diagnosis of dilated cardiomyopathy at age 11 years. A daughter died suddenly at the age of 2 months. A 4-year-old daughter, diagnosed with dilated cardiomyopathy at the time of birth, was found to have fetal left ventricular dilatation. mutations MYH7, PHE764LEU number 23 clinvarAccessions RCV000015165;;1 status live name CARDIOMYOPATHY, HYPERTROPHIC, MIDVENTRICULAR, DIGENIC text {16:Davis et al. (2001)} identified a double point mutation in the MYLK2 gene ({606566}) on the maternal haplotype in a 13-year-old white male proband with early midventricular hypertrophic cardiomyopathy (see {192600}). The MYLK2 mutations were ala87 to val (A87V; {606566.0001}) and ala95 to glu (A95E; {606566.0002}). The proband also inherited a glu743-to-asp mutation (E743D) in the beta-myosin gene (MYH7) from his father. Although the son had significant disease at an early age, the father and mother came to medical attention only after the diagnosis of the son. Echocardiographic evaluation showed that both parents had similarly abnormal asymmetrically thickened hearts. The kindred was too small for linkage analysis, and the authors proposed that the mutant MYLK2 may be functionally abnormal and may consequently stimulate cardiac hypertrophy. {16:Davis et al. (2001)} concluded that the increased severity of the disease at such a young age in the proband suggests a compound effect. mutations MYH7, GLU743ASP number 24 clinvarAccessions RCV000015166;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913644 text {7:Blair et al. (2001)} identified a C-to-T transition in exon 20 resulting in an ala728-to-val (A728V) mutation in cis with a val606-to-met (V606M; {160760.0005}) mutation in a family in which 3 individuals had suffered sudden death. {7:Blair et al. (2001)} suggested that this second mutation in cis with the V606M mutation was responsible for the more severe phenotype in this family. mutations MYH7, ALA728VAL number 25 clinvarAccessions RCV000015167;;1;;;RCV000035776;;1 status live name CARDIOMYOPATHY, DILATED, 1S dbSnps rs121913645 text In a series of 46 young patients with dilated cardiomyopathy-1S ({613426}), {12:Daehmlow et al. (2002)} identified 2 mutations in the MYH7 gene, one of which was a G-to-A transition in exon 8 at nucleotide 7799, resulting in an ala223-to-thr (A223T) substitution. The mutation affected a buried residue near the ATP-binding site. The patient with this mutation was 35 years old when diagnosed with dilated cardiomyopathy. mutations MYH7, ALA223THR number 26 clinvarAccessions RCV000015168;;1 status live name CARDIOMYOPATHY, DILATED, 1S dbSnps rs121913646 text In a series of 46 young patients with dilated cardiomyopathy-1S ({613426}), {12:Daehmlow et al. (2002)} found 2 mutations in the MYH7 gene, one of which was a C-to-T transition in exon 17 at nucleotide 12164, resulting in a ser642-to-leu (S642L) substitution at a highly conserved residue. The mutation occurred at the actin-myosin interface. The patient with this mutation was 18 years old when diagnosed with dilated cardiomyopathy. mutations MYH7, SER642LEU number 27 clinvarAccessions RCV000015169;;1 status live name MYOPATHY, MYOSIN STORAGE dbSnps rs28933098 text In affected members of a family and in an unrelated patient with myosin storage myopathy ({608358}) without cardiomyopathy, {71:Tajsharghi et al. (2003)} identified a heterozygous 23014C-T transition in the MYH7 gene, resulting in an arg1845-to-trp (R1845W) substitution. The mutation is located in the distal end of the filament-forming rod region of the protein. {71:Tajsharghi et al. (2003)} suggested that the mutation may interfere with the interaction of MYH7 with myosin-binding proteins and inhibit myosin assembly into thick filaments. {42:Laing et al. (2005)} identified the R1845W mutation in 2 unrelated Belgian patients with myosin storage myopathy. Neither patient had a family history of the disease. The mutation was predicted to impair the coiled-coil structure of the protein. {59:Pegoraro et al. (2007)} conducted MYH7 gene analysis by RT-PCR/SSCP/sequencing in 2 patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapuloperoneal myopathy of unknown etiology. They found the arg1845-to-trp mutation of the MYH7 gene in both cases of myosin storage myopathy and in 2 of the 17 scapuloperoneal patients ({181430}) studied. 5533C-T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in this cohort of patients included asymptomatic hyperCKemia (elevated serum creatine kinase), scapuloperoneal myopathy, and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. {59:Pegoraro et al. (2007)} concluded that phenotypic and histopathologic variability may underlie MYH7 gene mutation and that the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations. By functional analysis, {4:Armel and Leinwand (2009)} showed that the R1845W mutant protein was nearly indistinguishable from wildtype in both secondary structural characteristics and biophysical parameters. However, compared to the wildtype protein, the mutant protein was unable to assemble to the same extent, formed larger structures, and formed more stable paracrystals. The results suggested that the R1845W mutation alters the interactions between filaments such that their assembly is less constrained, causing the formation of abnormally large, degradation-resistant structures. Similar results were found for H1901L ({160760.0031}). mutations MYH7, ARG1845TRP number 28 alternativeNames SCAPULOPERONEAL MYOPATHY, MYH7-RELATED, INCLUDED clinvarAccessions RCV000015171;;1;;;RCV000015170;;1 status live name LAING DISTAL MYOPATHY dbSnps rs121913647 text In an Australian patient with sporadic Laing distal myopathy ({160500}), {51:Meredith et al. (2004)} identified an arg1500-to-pro (R1500P) mutation in exon 32 of the MYH7 gene. Mild talipes equinovarus had been noted at birth but corrected itself. By the time the patient was 4 years old, she was noted to have weakness of ankle dorsiflexion. Progressive weakness of legs and hands followed, with involvement of the arms at 11 years of age. mutations MYH7, ARG1500PRO number 29 clinvarAccessions RCV000015172;;1 status live name LAING DISTAL MYOPATHY dbSnps rs121913648 text In affected members of previously reported families with Laing distal myopathy ({160500}) from Germany ({77:Voit et al., 2001}) and Austria ({83:Zimprich et al., 2000}), {51:Meredith et al. (2004)} identified deletion of a lysine at position 1617 in exon 34 of the MYH7 gene. mutations MYH7, LYS1617DEL number 30 clinvarAccessions RCV000015173;;1;;;RCV000132753;;1 status live name MYOPATHY, MYOSIN STORAGE dbSnps rs121913649 text In affected members of a Saudi Arabian family with autosomal dominant hyaline body myopathy, or myosin storage myopathy ({608358}), reported by {9:Bohlega et al. (2003)}, {8:Bohlega et al. (2004)} identified a 25596A-T transversion in the MYH7 gene, resulting in a his1904-to-leu (H1904L) substitution in a highly conserved residue in the coiled-coil tail region of the protein. The mutation was not identified in 130 control chromosomes. None of the patients had cardiac abnormalities. The authors noted that the H1904L mutation is adjacent to a critical assembly competent domain and suggested that the mutation may cause improper assembly of the thick filament or interfere with stability of the protein. {57:Oldfors et al. (2005)} used a different numbering system and stated that the mutation described by {8:Bohlega et al. (2004)} should be HIS1901LEU. They asserted that the histidine at residue 1901 occupies the 'f' position of the heptad repeat of the coiled-coil domain, whereas residue 1904 is not at an 'f' position in the heptad repeat sequence. In response, {52:Meyer (2005)} stated that the mutation occupies an 'f' position regardless of the numbering system used. By functional analysis, {4:Armel and Leinwand (2009)}, who also referred to this mutation as H1901L, indicated that the mutant protein had decreased thermodynamic stability. In addition, the extent of assembly of the tail region was decreased compared to wildtype, and the paracrystals were much larger and more stable than wildtype. The findings suggested that the E1901L mutation alters the interactions between filaments such that larger, more stable structures are formed. Similar results were observed for R1845W ({160760.0028}). mutations MYH7, HIS1904LEU number 31 clinvarAccessions RCV000015174;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913650 text In 2 Danish patients with familial hypertrophic cardiomyopathy ({192600}), {31:Hougs et al. (2005)} identified a 21815C-T transition in exon 35 of the MYH7 gene, resulting in an arg1712-to-trp substitution (R1712W) in the myosin rod region. mutations MYH7, ARG1712TRP number 32 clinvarAccessions RCV000015175;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913651 text In a family with CMH ({192600}) previously reported by {28,29:Hengstenberg et al. (1993, 1994)}, {64:Richard et al. (1999)} found that of 8 affected members, 4 had a G-to-A transition in exon 15 of the MYH7 gene, leading to a glu483-to-lys (E483K) substitution; 2 had a G-to-T mutation at codon 1096 of the MYBPC3 gene ({600958.0014}) and 2 were doubly heterozygous for the 2 mutations. The E483K mutation was thought to affect a protein domain involved in actin fixation. mutations MYH7, GLU483LYS number 33 clinvarAccessions RCV000015176;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs36211715 text In 3 affected members of a large consanguineous Indian kindred with familial hypertrophic cardiomyopathy ({192600}), {72:Tanjore et al. (2006)} identified a G-to-A transition in exon 22 of the MYH7 gene, resulting in an arg870-to-his (R870H) substitution in the rod region. The 2 affected homozygotes had asymmetric septal hypertrophy without obstructive outflow, and one of them died of heart failure at age 37 years. The third patient was heterozygous for the R870H mutation and had hypertrophic cardiomyopathy with obstructive outflow. Analysis of family members identified the heterozygous R870H mutation in 18 individuals, of whom 10 were symptomatic. {72:Tanjore et al. (2006)} estimated the penetrance of the R870H mutation to be 59% in general, whereas 75% of males and 44% of females were clinically symptomatic, suggesting that female mutation carriers have a better prognosis. mutations MYH7, ARG870HIS number 34 clinvarAccessions RCV000015177;;1;;;RCV000035807;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913652 text In a 44-year-old male with hypertrophic cardiomyopathy and respiratory failure ({192600}), born of second-cousin British parents, {70:Tajsharghi et al. (2007)} identified homozygosity for a 24012G-A transition in exon 38 of the MYH7 gene, resulting in a glu1883-to-lys (E1883K) substitution at a highly conserved residue in the distal end of the filament-forming rod region. The proband had 2 similarly affected sibs who had died at ages 32 years and 57 years of cardiorespiratory failure; muscle biopsies from all 3 sibs showed findings typical for myosin storage myopathy ({608358}). The unaffected parents were presumed heterozygous carriers of the mutation, and another sib was unaffected. There was no family history of muscle weakness. By functional analysis, {4:Armel and Leinwand (2009)}, who referred to this mutation as E1886K, showed that the mutant protein showed no major differences in secondary structure or biophysical parameters from wildtype. However, that mutant protein had a decreased ability to assemble to the same extent as wildtype, and the paracrystals formed were more readily degraded by proteolysis. The authors concluded that altered packing of the filaments may destabilize them. mutations MYH7, GLU1883LYS number 35 alternativeNames MYOPATHY, MYOSIN STORAGE, INCLUDED clinvarAccessions RCV000015179;;1;;;RCV000015178;;1 status live name LAING DISTAL MYOPATHY dbSnps rs121913653 text In a Tanzanian boy with Laing distal myopathy ({160500}), {13:Darin et al. (2007)} identified a heterozygous 1408C-T transition in the MYH7 gene, resulting in a thr441-to-met (T441M) substitution in the globular head of the myosin heavy chain. The patient had distal muscle weakness in the lower limbs and mild atrial enlargement. {13:Darin et al. (2007)} noted that most patients with Laing myopathy have mutations in the rod region of the protein and suggested that the cardiac involvement in this child may be due to the mutation affecting the globular region. mutations MYH7, THR441MET number 36 clinvarAccessions RCV000035714;;1;;;RCV000015180;;1 status live name MYOPATHY, MYOSIN STORAGE dbSnps rs121913654 text In 1 of 2 sibs with myosin storage myopathy ({608358}) originally reported by {10:Cancilla et al. (1971)}, {18:Dye et al. (2006)} identified a heterozygous 5378T-C transition in exon 37 of the MYH7 gene, resulting in a leu1793-to-pro (L1793P) substitution in the light meromyosin (LMM) region of the myosin heavy chain tail. The sibs presumably had the disease because of gonadal mosaicism in 1 of the unaffected parents, although this could not be confirmed. By functional analysis, {4:Armel and Leinwand (2009)} showed that the L1793P mutation did not differ in protein secondary structure or in the alpha-helical content compared to wildtype, but decreased thermodynamic stability compared to wildtype. The L1793P mutation altered the ability of LMM to assemble, presumably because of the increased instability of the molecule. Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly. In a mother with myosin storage myopathy who later developed hypertrophic cardiomyopathy (CMH1; {192600}) and in her daughter who had early symptomatic left ventricular noncompaction (LVNC5; see {613426}), {74:Uro-Coste et al. (2009)} identified heterozygosity for the L1793P mutation in MYH7. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment, and she had some difficulty with heel-walking. mutations MYH7, LEU1793PRO number 37 alternativeNames CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1, INCLUDED;; LEFT VENTRICULAR NONCOMPACTION 5, INCLUDED clinvarAccessions RCV000015182;;1;;;RCV000015183;;1;;;RCV000015181;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs267606911 text In affected members of a family with hypertrophic cardiomyopathy-1 ({192600}), {2:Arad et al. (2005)} identified heterozygosity for a glu497-to-asp (E497D) substitution in the MYH7 gene. The proband had apical hypertrophy with associated electrocardiographic changes of left ventricular hypertrophy and deeply inverted precordial T waves, whereas a family member with concurrent coronary artery disease who carried the mutation had massive concentric hypertrophy with an interventricular septal thickness of 29 mm. mutations MYH7, GLU497ASP number 38 clinvarAccessions RCV000035727;;1;;;RCV000015184;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs267606908 text In 2 sibs with hypertrophic cardiomyopathy-1 ({192600}), {2:Arad et al. (2005)} identified heterozygosity for an asp906-to-gly (D906G) substitution in the MYH7 gene. The proband had apical hypertrophy, whereas the sib, who had sudden death at 45 years of age, was found on necropsy to have massive asymmetrical left ventricular hypertrophy with an interventricular septal thickness greater than 30 mm and a posterior left ventricular wall that was 18 mm thick. {2:Arad et al. (2005)} noted that the D906G mutation had previously been identified by {30:Ho et al. (2002)} in 22 affected members of a CMH family with a range of maximum left ventricular wall thickness of 13 to 29 mm; none had apical hypertrophy. mutations MYH7, ASP906GLY number 39 clinvarAccessions RCV000035817;;1;;;RCV000015185;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs267606910 text In a 40-year-old man with hypertrophic cardiomyopathy-1 ({192600}) who presented with presyncope and was found to have apical hypertrophy, {2:Arad et al. (2005)} identified heterozygosity for an arg243-to-his (R243H) substitution in the MYH7 gene. In affected members of a 3-generation family segregating autosomal dominant left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see {613426}), previously studied by {67:Sasse-Klaassen et al. (2003)} as 'family INVM-107,' {39:Klaassen et al. (2008)} identified heterozygosity for an 814G-A transition in the MYH7 gene, resulting in the R243H substitution. Noncompaction in all 4 affected individuals involved the apex and mid-left ventricular wall, and the right ventricle was involved as well in 2 patients. mutations MYH7, ARG243HIS number 40 alternativeNames LEFT VENTRICULAR NONCOMPACTION 5, INCLUDED clinvarAccessions RCV000015187;;1;;;RCV000015186;;1 status live name LEFT VENTRICULAR NONCOMPACTION 5 text In affected members of 2 families segregating autosomal dominant left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see {613426}), 1 of which was previously studied by {67:Sasse-Klaassen et al. (2003)} as 'family INVM-101,' {39:Klaassen et al. (2008)} identified heterozygosity for an 818+1G-A transition at the splice donor site in intron 8 of the MYH7 gene. The mutation segregated with disease in both families; haplotype analysis ruled out a founding mutation. Clinical evaluation in both families was remarkable for the very pronounced morphology of LVNC. The proband of family INVM-101 was diagnosed because of inverted T-waves and later had a stroke and systemic peripheral emboli, whereas his brother initially presented with decompensated heart failure and pulmonary emboli; both patients remained stable over a period of 8 years. Other affected members of family INVM-101 fulfilled morphologic LVNC criteria but were clinically asymptomatic. The proband of the other family was diagnosed because of atypical chest pain; he and his affected 8-year-old son had no signs of heart failure. mutations MYH7, IVS8DS, G-A, +1 number 41 clinvarAccessions RCV000015188;;1 status live name LEFT VENTRICULAR NONCOMPACTION 5 dbSnps rs267606909 text In a 20-year-old man with left ventricular noncompaction but no other congenital heart anomalies (LVNC5; see {613426}), {39:Klaassen et al. (2008)} identified heterozygosity for a de novo 5382G-A transition in exon 37 of the MYH7 gene, resulting in an ala1766-to-thr (A1766T) substitution. The proband was initially diagnosed due to arrhythmias on routine electrocardiogram, but his left ventricular systolic function subsequently deteriorated over a period of 6 years; sustained ventricular tachycardia resulted in implantation of an intracardiac defibrillator. The mutation was not present in his unaffected parents. mutations MYH7, ALA1766THR number 42 clinvarAccessions RCV000015189;;1 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1 dbSnps rs121913625 text In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, {21:Frazier et al. (2008)} identified heterozygosity for a 1357C-A transversion in exon 14 of the MYH7 gene, resulting in an arg453-to-ser (R453S) substitution, as well as a heterozygous missense mutation in the TNNI3 gene ({191044.0003}). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation. mutations MYH7, ARG453SER number 43 clinvarAccessions RCV000015190;;1 status live name LAING DISTAL MYOPATHY text In affected members of an Italian American family with Laing distal myopathy ({160500}) reported by {27:Hedera et al. (2003)}, {51:Meredith et al. (2004)} identified a heterozygous 3-bp deletion of 1 of 3 consecutive AAG triplets in exon 36 of the MYH7 gene, resulting in the deletion of lys1729 (lys1729del). {54:Muelas et al. (2010)} identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic and neurogenic features, and muscle biopsies showed fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy. {55:Muelas et al. (2012)} identified a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by {27:Hedera et al. (2003)}, indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. {55:Muelas et al. (2012)} hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin. mutations MYH7, 3-BP DEL, AAG number 44 clinvarAccessions RCV000015191;;1 status live name LEFT VENTRICULAR NONCOMPACTION 5 dbSnps rs397515482 text In affected individuals from 2 white families of western European descent segregating autosomal dominant left ventricular noncompaction (LVNC5; {613426}), {61:Postma et al. (2011)} identified heterozygosity for a mutation at nucleotide 933 in exon 10 of the MYH7 gene, resulting in a tyr283-to-asp (Y283D) substitution at a highly conserved residue. The mutation segregated with disease in both families and was not found in more than 980 ethnically matched control chromosomes. The 2 probands had other cardiac malformations in addition to LVNC, including Ebstein anomaly in both as well as type II atrial septal defect in 1 and pulmonary artery hypoplasia in the other. One family had 5 more affected individuals over 3 generations, 2 of whom had other cardiac malformations, including Ebstein anomaly in 1 and perimembranous ventricular septal defect in 1; 2 of the patients had only mild left ventricular apical hypertrabeculation. In the other family, the proband's asymptomatic mutation-positive father was found to have LVNC by screening echocardiography; in addition, a paternal aunt was reported to have heart failure, and the paternal grandfather had received an implantable cardioverter-defibrillator. mutations MYH7, TYR283ASP number 45 clinvarAccessions RCV000056316;;1 status live name LEFT VENTRICULAR NONCOMPACTION 5 text In 4 affected individuals over 3 generations of a white family of western European descent with left ventricular noncompaction (LVNC5; {613426}), {61:Postma et al. (2011)} identified heterozygosity for a mutation in exon 39 of the MYH7 gene, resulting in an asn1918-to-lys (N1918K) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in more than 980 ethnically matched control chromosomes. In addition to marked LVNC, the 39-year-old proband exhibited Ebstein anomaly, which was discovered upon evaluation of a cardiac murmur at 3 years of age. She remained asymptomatic despite significant tricuspid regurgitation from age 30 years. She had a mutation-positive son with bicuspid aortic valve and aortic coarctation in whom echocardiography at age 5 years also showed LVNC. Her asymptomatic mutation-positive mother and brother were both found to have LVNC by echocardiography, and her brother also had LV dilation with dysfunction. In an asymptomatic mutation-positive cousin, cardiomyopathy could not be ruled out due to poor imaging quality. mutations MYH7, ASN1918LYS number 46 clinvarAccessions RCV000056317;;1 prefix * titles alternativeTitles MYOSIN, CARDIAC, HEAVY CHAIN, BETA; MYHCB preferredTitle MYOSIN, HEAVY CHAIN 7, CARDIAC MUSCLE, BETA; MYH7 textSectionList textSection textSectionTitle Cloning textSectionContent The structural gene for the beta heavy chain of myosin is expressed predominantly in fetal life and is switched on in older animals under conditions of thyroid hormone depletion/replacement and in response to some physical stresses. {34:Jandreski et al. (1987)} presented evidence indicating that the cardiac beta-myosin heavy chain mRNA is expressed in skeletal muscle tissue. The expression of cardiac beta-myosin heavy chain mRNA was particularly prominent in the soleus muscle, which is rich in slow-twitch type I muscle fibers. There were only trace amounts in the vastus lateralis and vastus medialis, which consist predominantly of fast-twitch type II fibers. {17:Diederich et al. (1989)} cloned the entire gene. By scanning mouse myosin genes for intronic microRNAs (miRNAs), {75:van Rooij et al. (2009)} identified Mir208b ({613613}) within intron 31 of the Myh7 gene. Northern blot analysis showed that Myh7 and Mir208b were highly expressed in mouse slow-twitch soleus muscle. Little to no expression was detected in heart and in the fast-twitch gastrocnemius/plantaris, tibialis anterior, and extensor digitorum longus muscles. However, {75:van Rooij et al. (2009)} noted that Myh7 is the predominant myosin in adult heart in large animals, whereas Myh6 ({160710}) predominates in adult mouse heart. textSectionName cloning textSectionTitle Gene Structure textSectionContent {33:Jaenicke et al. (1990)} demonstrated that the MYH7 gene is 22,883 bp long. The 1,935 amino acids of this protein are encoded by 38 exons. The 5-prime untranslated region (86 bp) is split by 2 introns. The 3-prime untranslated region is 114 bp long. Three Alu repeats were identified within the gene and a fourth one in the 3-prime flanking intergenic region. {45:Liew et al. (1990)} found that like the rat skeletal myosin heavy chain gene, the cardiac beta-myosin heavy chain gene is divided into 41 exons, the first 2 of which are noncoding. However, exons 37 and 38 are fused; they do not have an intervening intron. The gene extends for 21,828 nucleotides and encodes a deduced 1,1939-amino acid protein with a molecular mass of 222,937 Da. {75:Van Rooij et al. (2009)} identified a microRNA (miRNA), Mir208b ({613613}), within intron 31 of the mouse Myh7 gene. textSectionName geneStructure textSectionTitle Mapping textSectionContent {48:Matsuoka et al. (1989)} found that both the alpha and the beta human cardiac myosin heavy chain genes are located in the 14cen-q13 region; the assignment was by somatic cell hybridization and in situ hybridization. {62:Qin et al. (1990)} localized the MYH7 gene to 14q12 by in situ hybridization. The beta cardiac myosin heavy chain is located on chromosome 14, 3.6 kb upstream from the alpha cardiac myosin gene. The 2 genes are oriented in a head-to-tail tandem fashion ({82:Yamauchi-Takihara et al., 1989}; {24:Geisterfer-Lowrance et al., 1990}). textSectionName mapping textSectionTitle Gene Function textSectionContent {76:Van Rooij et al. (2007)} found that miRNA208A (MIR208A; {611116}), a cardiac-specific miRNA encoded by intron 27 of the mouse and human MYH6 gene, was required for cardiomyocyte hypertrophy, fibrosis, and expression of Myh7 in response to stress and hypothyroidism in mice. {75:Van Rooij et al. (2009)} found that expression of Myh7 and its intronically encoded miRNA, Mir208b, was upregulated in mouse heart by hypothyroidism caused by inhibition of triiodothyronine (T3; see {188450}) synthesis. This upregulation was reversed by T3 administration. Gain- and loss-of-function experiments in mice showed that expression of Myh7 and Mir208b was controlled by the dominant miRNA in mouse heart, Mir208a. However, {75:van Rooij et al. (2009)} noted that, in large animals, Myh7 is the predominant myosin in adult heart. In contrast, the predominant myosin in adult mouse heart is Myh6, the host gene of Mir208a. Thus, {75:van Rooij et al. (2009)} suggested that Mir208b, which shares the same seed sequence as Mir208a, may fulfill the function of Mir208a in large animals. In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6; {160710}), whereas embryonic cardiomyocytes express beta-MHC (Myh7). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. {25:Hang et al. (2010)} showed that BRG1 ({603254}), a chromatin-remodeling protein, has a critical role in regulating cardiac growth, differentiation, and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 ({608748}) and suppressing p57(kip2) ({600856}) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylases (HDACs; see {601241}) and poly(ADP ribose) polymerase (PARP; {173870}) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1 reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. {25:Hang et al. (2010)} concluded that their studies showed that BRG1 maintains cardiomyocytes in an embryonic state, and demonstrated an epigenetic mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC, and PARP, cooperate to control developmental and pathologic gene expression. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Hypertrophic Cardiomyopathy 1 {50:McKenna (1993)} estimated that 40 to 50% of cases of hypertrophic cardiomyopathy (CMH; {192600}) are due to mutations in the MYH7 gene. He stated that Kaplan-Meier survival curves for these mutations showed that the val606-to-met mutation ({160760.0005}) was associated with normal survivorship, whereas the arg453-to-cys mutation ({160760.0003}) was associated with death in about half the affected individuals by age 40 years. {1:Anan et al. (1994)} presented a schematic of 15 mutations within the MYH7 gene that cause CMH. They described a phe513-to-cys mutation ({160760.0016}) in which affected family members had near-normal life expectancy, and an arg719-to-trp mutation ({160760.0017}) in 4 unrelated CMH families with a high incidence of premature death and an average life expectancy in affected individuals of 38 years. They suggested that these findings supported the hypothesis that mutations that alter the charge of the encoded amino acid affects survival more significantly than those that produce a conservative amino acid change. {38:Kelly and Strauss (1994)} pointed out that all but one of the known mutations of the MYH7 gene that produce hypertrophic cardiomyopathy result in amino acid substitutions in the protein head or the region in which the head and rod of the molecule intersect. In their Figure 2, they diagrammed the cardiac myosin heavy-chain dimer and the site of the mutations. They suggested that these mutations represent dominant negatives by disturbing contractile function despite the production of a normal protein by the remaining normal allele. Consistent with this conclusion is the finding of {11:Cuda et al. (1993)} that mutant beta-myosin separated from the heart muscle in cases of hypertrophic cardiomyopathy of the chromosome 14 type translocate actin filaments with an abnormally low sliding velocity in motility assays in vitro. {44:Lankford et al. (1995)} compared the contractile properties of single slow-twitch muscle fibers from patients with 3 distinct CMH-causing MYH7 mutations with those from normal controls. Fibers from the gly741-to-arg mutation ({160760.0011}), located near the binding site of essential light chain, demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal). Fibers with the arg403-to-gln mutation ({160760.0001}) (at the actin interface of myosin) showed lower force/stiffness ratio (56% of normal) and depressed velocity of shortening (50% of normal). Both of these mutation-containing fibers displayed abnormal force-velocity relationships and reduced power output. Fibers from the gly256-to-glu mutation ({160760.0012}), located at the end of the ATP-binding pocket, had contractile properties that were indistinguishable from normal. Thus, variability was found in the nature and extent of functional impairments in skeletal fibers containing different MYH7 gene mutations, and this variability may correlate with the severity and penetrance of the disease resulting from each mutation. {63:Rayment et al. (1995)} examined 29 missense mutations in the MYH7 gene that are responsible for 10 to 30% of familial hypertrophic cardiomyopathy cases and analyzed their effects on the 3-dimensional structure of skeletal muscle myosin. {3:Arai et al. (1995)} reported a thirtieth missense mutation and stated that these had been found in 49 families worldwide at that time. Almost all were located in the region of the gene coding for the globular head of the molecule and only 1 mutation was found in both Caucasian and Japanese families. {68:Seidman (2000)} pointed out that correlations between genotype and prognosis in hypertrophic cardiomyopathy is possible. Life expectancy is markedly diminished in individuals with the R719W ({160760.0017}) and R403Q ({160760.0001}) mutations in the MYH7 gene but near normal in individuals with the E542Q ({600958.0006}) and 791insG ({600958.0011}) mutations in the MYBPC3 gene. {81:Woo et al. (2003)} screened 70 probands with hypertrophic cardiomyopathy for mutations in the beta-MHC gene. Mutations in this gene were detected in 15 of 70 probands (21%). Eleven mutations were detected, including 4 novel mutations. Median survival was 66 years (95% CI 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain. Significant independent predictors of decreased survival were the nonconservative missense mutations that affected the actin binding site and those that affected the rod portion of beta-MHC. {31:Hougs et al. (2005)} screened for mutations in the rod region (exons 24 to 40) of MYH7 in 92 Danish patients with hypertrophic cardiomyopathy. Using capillary electrophoresis single-strand conformation polymorphism, 3 disease-causing mutations of the rod region were identified in 4 patients, including the R1712W ({160760.0032}) mutation in 2 patients. Two of the patients had already been shown to carry other FHC-associated mutations. {2:Arad et al. (2005)} identified 2 different MYH7 missense mutations in 2 probands with apical hypertrophy from families in which the mutations also caused other CMH morphologies (see {160760.0038} and {160760.0039}, respectively), and 1 in a sporadic patient with apical hypertrophy (R243H; {160760.0040}). In a consanguineous British family in which 3 sibs developed hypertrophic cardiomyopathy, respiratory failure, and myosin storage myopathy ({608358}), {70:Tajsharghi et al. (2007)} identified homozygosity for a missense mutation in the MYH7 gene ({160760.0035}). In a Japanese proband with CMH (CMH17; {613873}), {49:Matsushita et al. (2007)} identified heterozygosity for a missense mutation in the JPH2 gene ({605267.0004}); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 mutations in MYH7, F513C ({160760.0016}) and A26V. The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, {21:Frazier et al. (2008)} identified a heterozygous mutation in the TNNI3 gene (P82S; {191044.0003}) and a heterozygous mutation in the MYH7 gene (R453S; {160760.0043}). From 2000 to 2012, {14:Das et al. (2014)} studied a total of 136 unrelated hypertrophic cardiomyopathy probands, of which 63 (46%) carried at least 1 pathogenic mutation. MYBPC3 ({600958}) accounted for 34 patients, or 47%, and MYH7 accounted for 23 patients, or 32%. Together, these gene variants accounted for 79%. In this study, 5 variants in 6 probands (10%) were reclassified: 2 variants of uncertain significance were upgraded to pathogenic, 1 variant of uncertain significance and 1 pathogenic variant were downgraded to benign, and 1 pathogenic variant (found in 2 families) was downgraded to a variant of uncertain significance. {14:Das et al. (2014)} concluded that given the rapid growth of genetic information available, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy. Dilated Cardiomyopathy 1S {37:Kamisago et al. (2000)} performed clinical evaluations in 21 kindreds with familial dilated cardiomyopathy (CMD1S; {613426}). In a genomewide linkage study, a genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-q13 (maximum lod score = 5.11 at theta = 0.0). Analysis of MYH7 and other genes for sarcomere proteins revealed heterozygous missense mutations in MYH7 in 2 kindreds (S532P, {160760.0022} and P764L, {160760.0023}, respectively). Affected individuals had neither antecedent cardiac hypertrophy nor histopathologic findings characteristic of hypertrophy. Myosin Storage Myopathy, Laing Distal Myopathy, and Scapuloperoneal Myopathy In affected members of a family and in an unrelated patient with myosin storage myopathy ({608358}), {71:Tajsharghi et al. (2003)} identified a heterozygous mutation in the MYH7 gene ({160760.0028}). {43:Laing et al. (1995)} mapped Laing distal myopathy ({160500}) to chromosome 14. In affected members of 7 separate families with Laing distal myopathy, {51:Meredith et al. (2004)} sequenced the MYH7 gene, a positional candidate for the site of the causative mutation. They identified 5 heterozygous mutations in 6 families (see {160760.0029}-{160760.0030}) and no mutations in the seventh family. All 5 mutations were predicted, by in silico analysis, to disrupt locally the ability of the myosin tail to form a coiled coil, which is its normal structure. The findings demonstrated that heterozygous mutations toward the 3-prime end of MYH7 can cause Laing distal myopathy. {59:Pegoraro et al. (2007)} conducted MYH7 gene analysis by RT-PCR/SSCP/sequencing in 2 patients diagnosed with myosin storage myopathy and 17 patients diagnosed with scapuloperoneal myopathy of unknown etiology. They found the R1845W mutation of the MYH7 gene in both cases of myosin storage myopathy and in 2 of the 17 scapuloperoneal patients ({181430}) studied. 5533C-T segregation analysis in the mutation carrier families identified 11 additional patients. The clinical spectrum in this cohort of patients included asymptomatic hyperCKemia (elevated serum creatine kinase), scapuloperoneal myopathy, and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies characteristic of myosin storage myopathy in only half of biopsied patients (2 of 4). These patients without hyaline bodies had been diagnosed with scapuloperoneal myopathy prior to the identification of hyaline bodies in other family members, prompting MYH7 gene analysis. The authors pointed out that patients without hyaline bodies presented later onset and milder severity. {4:Armel and Leinwand (2009)} analyzed the functional effects of 4 different MYH7 mutations in the rod or tail domain that were found to be responsible for myosin storage myopathy: R1845W ({160760.0028}), H1901L ({160760.0031}), E1886K ({160760.0035}), and L1793P ({160760.0037}). None of the mutations altered the secondary structure of the protein, but L1793P and H1901L showed decreased thermodynamic stability. All mutations decreased the extent of self-assembly of the light meromyosin rod (less than 50 to 60%) compared to the wildtype protein. R1845W and H1901L showed formation of more stable and larger filaments, whereas L1793P and E1886K showed more rapid filament degradation. {4:Armel and Leinwand (2009)} noted that the assembly of muscle filaments is a multistep process that involves both the proper folding of alpha-helices into coiled-coils, and the assembly of these coiled-coils, in proper register, into filaments, and concluded that defects in any one of these steps can result in improper filament formation leading to muscle disease. Left Ventricular Noncompaction 5 {39:Klaassen et al. (2008)} analyzed 6 genes encoding sarcomere proteins in 63 unrelated adult probands with left ventricular noncompaction (LVNC) but no other congenital heart anomalies (see LVNC5; {613426}), and identified 7 different heterozygous mutations in the MYH7 gene in the probands from 4 families and in 4 sporadic patients (see, e.g., {160760.0040}-{160760.0042}). {39:Klaassen et al. (2008)} noted that 5 of the 7 mutations were located within the genomic sequence of exon 8 to exon 9 of MYH7, which appeared to be a cluster for LVNC mutations. In a mother with myosin storage myopathy, who later developed CMH, and in her daughter, who had early-symptomatic LVNC, {74:Uro-Coste et al. (2009)} identified heterozygosity for the L1793P mutation in MYH7 ({160760.0037}). In an analysis of the MYH7 gene in 141 white probands of western European descent diagnosed with Ebstein anomaly (see {224700}), {61:Postma et al. (2011)} identified heterozygous mutations in 8 (see, e.g., {160760.0045} and {160760.0046}). Of these 8 probands, LVNC was present in 7 and uncertain in 1, whereas none of the 133 mutation-negative probands had LVNC. Evaluation of all available family members of mutation-positive probands revealed 3 families in which additional mutation-positive individuals had cardiomyopathy or congenital heart malformations, including type II atrial septal defect, ventricular septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary artery stenosis/hypoplasia. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {23:Geisterfer-Lowrance et al. (1996)} engineered the human CMH cardiac myosin heavy chain gene mutation arg403-to-gln (R403Q) into the mouse genome to create a murine model of familial hypertrophic cardiomyopathy. Homozygous mice died within a week after birth, while heterozygous mice displayed both histologic and hemodynamic abnormalities characteristic of CMH. In addition, the CMH mice demonstrated gender and developmental differences. Male CMH mice demonstrated more severe myocyte hypertrophy, disarray, and interstitial fibrosis than their female littermates, and both sexes showed increased cardiac dysfunction and histopathology as they aged. Heterozygous CMH mice also had sudden death of uncertain etiology, especially during periods of exercise. {6:Berul et al. (1997)} found that in contrast to wildtype mice which had completely normal cardiac electrophysiology, CMH mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiologic abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. {20:Fatkin et al. (1999)} reported further studies of the CMH mouse in which the arg403-to-gln mutation had been introduced by homologous recombination. Heterozygous mice developed myocardial histologic abnormalities similar to those in human CMH by 15 weeks of age. Sedentary heterozygous mice had a normal life span. Homozygous mutant mice were liveborn, but, unlike their heterozygous littermates, all died within 1 week. {20:Fatkin et al. (1999)} found that neonatal lethality was caused by a fulminant dilated cardiomyopathy characterized by myocyte dysfunction and loss. They studied cardiac dimensions and functions for the first time in neonatal mice by high frequency (45 MHz) echocardiography and found that both were normal at birth. Between days 4 and 6, homozygous deficient mice developed a rapidly progressive cardiomyopathy with left ventricular dilation, wall thinning, and reduced systolic contraction. Histopathology revealed myocardial necrosis with dystrophic calcification. Electron microscopy showed normal architecture intermixed with focal myofibrillar disarray. {20:Fatkin et al. (1999)} speculated that variable incorporation of mutant and normal MYHC into sarcomeres of heterozygotes may account for focal myocyte death in familial hypertrophic cardiomyopathy. In R403Q-knockin mice, {22:Gao et al. (1999)} observed that during twitch contractions, peak intracellular Ca(2+) was higher in mutant muscles than in wildtype muscles, but force development was equivalent in both. Developed force fell at higher stimulation rates in the mutants but not in controls. {22:Gao et al. (1999)} concluded that calcium cycling and myofilament properties are both altered in CMH mutant mice. {46:Marian et al. (1999)} created a transgenic rabbit model of hypertrophic cardiomyopathy by injecting a transgene carrying the R403Q mutation into fertilized zygotes. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in the myocardium. Mean septal thickness was comparable between rabbits carrying the wildtype transgene and nontransgenic littermates, but was significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wildtype transgenic rabbits or in nontransgenic littermates. Thus, the phenotype of patients with the R403Q mutation of the MYH7 was reproduced. To minimize confounding variables while assessing relationships between CMH histopathology and arrhythmia vulnerability, {80:Wolf et al. (2005)} generated inbred CMH mice carrying the R403Q mutation and observed variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of fibrosis and myocyte disarray. There was no correlation between the amount and/or pattern of fibrosis or the quantity of myocyte disarray and the propensity for arrhythmia as assessed by ex vivo high-resolution mapping and in vivo electrophysiologic study; however, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. {80:Wolf et al. (2005)} concluded that the 3 cardinal manifestations of CMH (cardiac hypertrophy, myocyte fibrosis, and disarray) reflect independent pathologic processes within myocytes carrying a sarcomere gene mutation and that the severity of fibrosis and disarray is substantially influenced by unknown somatic factors, and they suggested that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in CMH. The human hypertrophic cardiomyopathy-causing mutation MYH7 R403Q ({160760.0001}) causes particularly severe disease characterized by early-onset and progressive myocardial dysfunction, with a high incidence of cardiac sudden death. MHC(403/+) mice express an R403Q mutation in Myh6 ({160710}) under the control of the endogenous Myh locus. {36:Jiang et al. (2013)} found that expression of the Myh6 R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of hypertrophic cardiomyopathy, for at least 6 months. Because inhibition of hypertrophic cardiomyopathy was achieved by only a 25% reduction in the levels of mutant transcripts, {36:Jiang et al. (2013)} suggested that the variable clinical phenotype in hypertrophic cardiomyopathy patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit. textSectionName animalModel geneMapExists true editHistory alopez : 04/28/2014 alopez : 1/29/2014 carol : 10/9/2013 carol : 10/8/2013 carol : 9/4/2013 carol : 4/1/2013 terry : 5/10/2012 carol : 5/9/2012 ckniffin : 5/3/2012 mgross : 8/9/2011 wwang : 4/7/2011 terry : 4/7/2011 wwang : 11/29/2010 ckniffin : 10/26/2010 mgross : 10/25/2010 mgross : 10/25/2010 mgross : 10/25/2010 terry : 10/6/2010 alopez : 9/28/2010 alopez : 9/28/2010 alopez : 9/28/2010 terry : 9/27/2010 wwang : 8/9/2010 terry : 8/5/2010 carol : 6/8/2010 carol : 6/8/2010 carol : 6/7/2010 carol : 6/7/2010 wwang : 10/26/2009 ckniffin : 10/14/2009 ckniffin : 10/14/2009 terry : 3/4/2009 alopez : 2/21/2008 alopez : 2/21/2008 alopez : 2/20/2008 terry : 2/19/2008 wwang : 1/17/2008 ckniffin : 1/7/2008 carol : 12/6/2007 carol : 12/4/2007 terry : 12/4/2007 carol : 11/26/2007 terry : 11/21/2007 carol : 9/4/2007 alopez : 6/15/2007 alopez : 6/12/2007 terry : 6/4/2007 wwang : 6/13/2006 ckniffin : 5/31/2006 carol : 4/18/2006 carol : 2/27/2006 joanna : 2/24/2006 joanna : 2/24/2006 wwang : 2/23/2006 terry : 1/17/2006 carol : 8/12/2005 terry : 7/13/2005 carol : 7/1/2005 wwang : 6/30/2005 ckniffin : 6/27/2005 wwang : 6/15/2005 wwang : 6/14/2005 ckniffin : 6/9/2005 wwang : 6/6/2005 ckniffin : 5/18/2005 wwang : 4/28/2005 wwang : 4/20/2005 terry : 4/11/2005 tkritzer : 2/2/2005 ckniffin : 1/25/2005 tkritzer : 9/9/2004 terry : 9/9/2004 cwells : 1/20/2004 terry : 1/15/2004 tkritzer : 12/31/2003 ckniffin : 12/24/2003 carol : 5/9/2003 terry : 5/9/2003 tkritzer : 5/7/2003 cwells : 3/12/2003 terry : 3/7/2003 carol : 11/12/2002 carol : 11/12/2002 tkritzer : 11/11/2002 terry : 11/5/2002 tkritzer : 8/2/2002 carol : 3/1/2002 mgross : 12/17/2001 carol : 1/11/2001 cwells : 1/11/2001 cwells : 1/9/2001 terry : 1/4/2001 mcapotos : 2/2/2000 mcapotos : 2/1/2000 terry : 1/19/2000 mgross : 11/24/1999 terry : 11/15/1999 carol : 10/28/1999 alopez : 4/30/1999 dkim : 12/10/1998 carol : 6/9/1998 carol : 6/9/1998 terry : 5/18/1998 alopez : 5/14/1998 dholmes : 5/7/1998 mark : 3/3/1998 mark : 12/26/1996 mark : 4/16/1996 terry : 4/9/1996 mark : 9/14/1995 davew : 8/5/1994 jason : 6/13/1994 warfield : 4/21/1994 carol : 4/2/1994 carol : 9/24/1993 dateCreated Mon, 02 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/2/1986 epochUpdated 1398668400 dateUpdated Mon, 28 Apr 2014 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1172/JCI116957 publisherName Journal of Clinical Investigation title Prognostic implications of novel beta-cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 1 publisherAbbreviation JCI pubmedID 8282798 source J. Clin. Invest. 93: 280-285, 1994. authors Anan, R., Greve, G., Thierfelder, L., Watkins, H., McKenna, W. J., Solomon, S., Vecchio, C., Shono, H., Nakao, S., Tanaka, H., Mares, A., Jr., Towbin, J. A., Spirito, P., Roberts, R., Seidman, J. G., Seidman, C. 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A. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI117795 publisherName Journal of Clinical Investigation title Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 44 publisherAbbreviation JCI pubmedID 7883988 source J. Clin. Invest. 95: 1409-1414, 1995. authors Lankford, E. B., Epstein, N. D., Fananapazir, L., Sweeney, H. L. pubmedImages false publisherUrl http://www.jci.org articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2362820 publisherName HighWire Press title Complete sequence and organization of the human cardiac beta-myosin heavy chain gene. mimNumber 160760 referenceNumber 45 publisherAbbreviation HighWire pubmedID 2362820 source Nucleic Acids Res. 18: 3647-3651, 1990. authors Liew, C.-C., Sole, M. J., Yamauchi-Takihara, K., Kellam, B., Anderson, D. H., Lin, L., Liew, J. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI7956 publisherName Journal of Clinical Investigation title A transgenic rabbit model for human hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 46 publisherAbbreviation JCI pubmedID 10606622 source J. Clin. Invest. 104: 1683-1692, 1999. authors Marian, A. J., Wu, Y., Lim, D.-S., McCluggage, M., Youker, K., Yu, Q., Brugada, R., DeMayo, F., Quinones, M., Roberts, R. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI116101 publisherName Journal of Clinical Investigation title Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 47 publisherAbbreviation JCI pubmedID 1361491 source J. Clin. Invest. 90: 2156-2165, 1992. authors Marian, A. J., Yu, Q.-T., Mares, A., Jr., Hill, R., Roberts, R., Perryman, M. B. pubmedImages false publisherUrl http://www.jci.org source Cytogenet. Cell Genet. 51: 1040-1041, 1989. mimNumber 160760 authors Matsuoka, R., Yoshida, M. C., Kanda, N., Kimura, M., Ozasa, H., Takao, A. title Human cardiac myosin heavy-chain gene mapped within chromosomal region 14q11.2-q13. (Abstract) referenceNumber 48 title Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 49 pubmedID 17476457 source J. Hum. Genet. 52: 543-548, 2007. authors Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. pubmedImages false source London, England 5/30/1993. mimNumber 160760 authors McKenna, W. J. title Personal Communication. referenceNumber 50 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62722-0 publisherName Elsevier Science title Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). mimNumber 160760 referenceNumber 51 publisherAbbreviation ES pubmedID 15322983 source Am. J. Hum. Genet. 75: 703-708, 2004. authors Meredith, C., Herrmann, R., Parry, C., Liyanage, K., Dye, D. E., Durling, H. J., Duff, R. M., Beckman, K., de Visser, M., van der Graaff, M. M., Hedera, P., Fink, J. K., Petty, E. M., Lamont, P., Fabian, V., Bridges, L., Voit, T., Mastaglia, F. L., Laing, N. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15706639 publisherName HighWire Press title Reply to Oldfors et al. (Letter) mimNumber 160760 referenceNumber 52 publisherAbbreviation HighWire pubmedID 15706639 source Neurology 64: 581 only, 2005. authors Meyer, B. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62137-5 publisherName Elsevier Science title The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. mimNumber 160760 referenceNumber 53 publisherAbbreviation ES pubmedID 10521296 source Am. J. Hum. Genet. 65: 1308-1320, 1999. authors Moolman-Smook, J. C., De Lange, W. J., Bruwer, E. C. D., Brink, P. A., Corfield, V. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=20733148 publisherName HighWire Press title MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. mimNumber 160760 referenceNumber 54 publisherAbbreviation HighWire pubmedID 20733148 source Neurology 75: 732-741, 2010. authors Muelas, N., Hackman, P., Luque, H., Garces-Sanchez, M., Azorin, I., Suominen, T., Sevilla, T., Mayordomo, F., Gomez, L., Marti, P., Maria Millan, J., Udd, B., Vilchez, J. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2012&volume=81&issue=5&spage=491 publisherName Blackwell Publishing title Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients. mimNumber 160760 referenceNumber 55 publisherAbbreviation Blackwell pubmedID 21395566 source Clin. Genet. 81: 491-494, 2012. authors Muelas, N., Hackman, P., Luque, H., Suominen, T., Espinos, C., Garces-Sanchez, M., Sevilla, T., Azorin, I., Millan, J. M., Udd, B., Vilchez, J. J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X84714835 publisherName Elsevier Science title Possible gene dose effect of a mutant cardiac beta-myosin heavy chain gene on the clinical expression of familial hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 56 publisherAbbreviation ES pubmedID 7909436 source Biochem. Biophys. Res. Commun. 200: 549-556, 1994. authors Nishi, H., Kimura, A., Harada, H., Adachi, K., Koga, Y., Sasazuki, T., Toshima, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15699411 publisherName HighWire Press title Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. (Letter) mimNumber 160760 referenceNumber 57 publisherAbbreviation HighWire pubmedID 15699411 source Neurology 64: 580-581, 2005. authors Oldfors, A., Tajsharghi, H., Thornell, L. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Hereditary cardiovascular dysplasia: a form of familial cardiomyopathy. mimNumber 160760 referenceNumber 58 pubmedID 13732753 source Am. J. Med. 31: 37-62, 1961. authors Pare, J. A. P., Fraser, R. G., Pirozynski, W. J., Shanks, J. A., Stubington, D. pubmedImages false source Neuromuscular Disord. 17: 321-329, 2007. mimNumber 160760 authors Pegoraro, E., Gavassini, B. F., Borsato, C., Melacini, P., Vianello, A., Stramere, R., Cenacchi, G., Angelini, C. title MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. referenceNumber 59 articleUrl http://dx.doi.org/10.1172/JCI115848 publisherName Journal of Clinical Investigation title Expression of a missense mutation in the messenger RNA for beta-myosin heavy chain in myocardial tissue in hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 60 publisherAbbreviation JCI pubmedID 1634614 source J. Clin. Invest. 90: 271-277, 1992. authors Perryman, M. B., Yu, Q., Marian, A. J., Mares, A., Jr., Czernuszewicz, G., Ifegwu, J., Hill, R., Roberts, R. pubmedImages false publisherUrl http://www.jci.org articleUrl http://circgenetics.ahajournals.org/cgi/pmidlookup?view=long&pmid=21127202 publisherName HighWire Press title Mutations in the sarcomere gene MYH7 in Ebstein anomaly. mimNumber 160760 referenceNumber 61 publisherAbbreviation HighWire pubmedID 21127202 source Circ. Cardiovasc. Genet. 4: 43-50, 2011. authors Postma, A. V., van Engelen, K., van de Meerakker, J., Rahman, T., Probst, S., Baars, M. J. H., Bauer, U., Pickardt, T., Sperling, S. R., Berger, F., Moorman, A. F. M., Mulder, B. J. M., Thierfelder, L., Keavney, B., Goodship, J., Klaassen, S. pubmedImages false publisherUrl http://highwire.stanford.edu title Localization of human cardiac beta-myosin heavy chain gene (MYH7) to chromosome 14q12 by in situ hybridization. mimNumber 160760 referenceNumber 62 pubmedID 2249479 source Cytogenet. Cell Genet. 54: 74-76, 1990. authors Qin, H., Kemp, J., Yip, M.-Y., Lam-Po-Tang, P. R. L., Hoh, J. F. Y., Morris, B. J. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7731997 publisherName HighWire Press title Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 63 publisherAbbreviation HighWire pubmedID 7731997 source Proc. Nat. Acad. Sci. 92: 3864-3868, 1995. authors Rayment, I., Holden, H. M., Sellers, J. R., Fananapazir, L., Epstein, N. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10424815 publisherName HighWire Press title Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 64 publisherAbbreviation HighWire pubmedID 10424815 source J. Med. Genet. 36: 542-545, 1999. authors Richard, P., Isnard, R., Carrier, L., Dubourg, O., Donatien, Y., Mathieu, B., Bonne, G., Gary, F., Charron, P., Hagege, A., Komajda, M., Schwartz, K., Hainque, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/1050-1738(92)90036-R publisherName Elsevier Science title Two brothers with unexplained cardiomegaly: initial clues to the molecular basis of a hereditary cardiac disease. mimNumber 160760 referenceNumber 65 publisherAbbreviation ES pubmedID 21239280 source Trends Cardiovasc. Med. 2: 2-5, 1992. authors Ross, R. S., Knowlton, K. U. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3037493 publisherName HighWire Press title Human cardiac myosin heavy chain genes and their linkage in the genome. mimNumber 160760 referenceNumber 66 publisherAbbreviation HighWire pubmedID 3037493 source Nucleic Acids Res. 15: 5443-5459, 1987. authors Saez, L. J., Gianola, K. M., McNally, E. M., Feghali, R., Eddy, R., Shows, T. B., Leinwand, L. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.20075 publisherName John Wiley & Sons, Inc. title Isolated noncompaction of the left ventricular myocardium in the adult is an autosomal dominant disorder in the majority of patients. mimNumber 160760 referenceNumber 67 publisherAbbreviation Wiley pubmedID 12749056 source Am. J. Med. Genet. 119A: 162-167, 2003. authors Sasse-Klaassen, S., Gerull, B., Oechslin, E., Jenni, R., Thierfelder, L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source J. Clin. Invest. 106: S9-S13, 2000. mimNumber 160760 authors Seidman, C. title Hypertrophic cardiomyopathy: from man to mouse. referenceNumber 68 articleUrl http://dx.doi.org/10.1172/JCI1940 publisherName Journal of Clinical Investigation title Diastolic dysfunction and altered energetics in the alpha-MHC-403/+ mouse model of familial hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 69 publisherAbbreviation JCI pubmedID 9541509 source J. Clin. Invest. 101: 1775-1783, 1998. authors Spindler, M., Saupe, K. W., Christe, M. E., Sweeney, H. L., Seidman, C. E., Seidman, J. G., Ingwall, J. S. pubmedImages false publisherUrl http://www.jci.org articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=17372140 publisherName HighWire Press title Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy. mimNumber 160760 referenceNumber 70 publisherAbbreviation HighWire pubmedID 17372140 source Neurology 68: 962 only, 2007. authors Tajsharghi, H., Oldfors, A., Macleod, D. P., Swash, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.10693 publisherName John Wiley & Sons, Inc. title Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. mimNumber 160760 referenceNumber 71 publisherAbbreviation Wiley pubmedID 14520662 source Ann. Neurol. 54: 494-500, 2003. authors Tajsharghi, H., Thornell, L.-E., Lindberg, C., Lindvall, B., Henriksson, K.-G., Oldfors, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2006&volume=69&issue=5&spage=434 publisherName Blackwell Publishing title Genotype-phenotype correlation of R870H mutation in hypertrophic cardiomyopathy. (Letter) mimNumber 160760 referenceNumber 72 publisherAbbreviation Blackwell pubmedID 16650083 source Clin. Genet. 69: 434-436, 2006. authors Tanjore, R. R., Sikindlapuram, A. D., Calambur, N., Thakkar, B., Kerkar, P. G., Nallari, P. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022282896903326 publisherName Elsevier Science title The influence of the angiotensin I converting enzyme genotype in familial hypertrophic cardiomyopathy varies with the disease gene mutation. mimNumber 160760 referenceNumber 73 publisherAbbreviation ES pubmedID 9140839 source J. Molec. Cell Cardiol. 29: 831-838, 1997. authors Tesson, F., Dufour, C., Moolman, J. C., Carrier, L., Al-Mahdawi, S., Chojnowska, L., Dubourg, O., Soubrier, F., Brink, P., Komajda, M., Guicheney, P., Schwartz, K., Feingold, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0960-8966(08)00710-4 publisherName Elsevier Science title Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 leu1793pro mutation. mimNumber 160760 referenceNumber 74 publisherAbbreviation ES pubmedID 19138847 source Neuromusc. Disord. 19: 163-166, 2009. authors Uro-Coste, E., Arne-Bes, M.-C., Pellissier, J.-F., Richard, P., Levade, T., Heitz, F., Figarella-Branger, D., Delisle, M.-B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1534-5807(09)00435-3 publisherName Elsevier Science title A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. mimNumber 160760 referenceNumber 75 publisherAbbreviation ES pubmedID 19922871 source Dev. Cell 17: 662-673, 2009. authors van Rooij, E., Quiat, D., Johnson, B. A., Sutherland, L. B., Qi, X., Richardson, J. A., Kelm, R. J., Jr., Olson, E. N. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=17379774 publisherName HighWire Press title Control of stress-dependent cardiac growth and gene expression by a microRNA. mimNumber 160760 referenceNumber 76 publisherAbbreviation HighWire pubmedID 17379774 source Science 316: 575-579, 2007. authors van Rooij, E., Sutherland, L. B., Qi, X., Richardson, J. A., Hill, J., Olson, E. N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0960896600001589 publisherName Elsevier Science title Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus. mimNumber 160760 referenceNumber 77 publisherAbbreviation ES pubmedID 11166161 source Neuromusc. Disord. 11: 11-19, 2001. authors Voit, T., Kutz, P., Leube, B., Neuen-Jacob, E., Schroder, J. M., Cavallotti, D., Vaccario, M. L., Schaper, J., Broich, P., Cohn, R., Baethmann, M., Gohlich-Ratmann, G., Scoppetta, C., Herrmann, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199204233261703?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. mimNumber 160760 referenceNumber 78 publisherAbbreviation ATYPON pubmedID 1552912 source New Eng. J. Med. 326: 1108-1114, 1992. authors Watkins, H., Rosenzweig, A., Hwang, D.-S., Levi, T., McKenna, W., Seidman, C. E., Seidman, J. G. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1172/JCI116038 publisherName Journal of Clinical Investigation title Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. mimNumber 160760 referenceNumber 79 publisherAbbreviation JCI pubmedID 1430197 source J. Clin. Invest. 90: 1666-1671, 1992. authors Watkins, H., Thierfelder, L., Hwang, D.-S., McKenna, W., Seidman, J. G., Seidman, C. E. pubmedImages false publisherUrl http://www.jci.org articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16332958 publisherName HighWire Press title Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia. mimNumber 160760 referenceNumber 80 publisherAbbreviation HighWire pubmedID 16332958 source Proc. Nat. Acad. Sci. 102: 18123-18128, 2005. authors Wolf, C. M., Moskowitz, I. P. G., Arno, S., Branco, D. M., Semsarian, C., Bernstein, S. A., Peterson, M., Maida, M., Morley, G. E., Fishman, G., Berul, C. I., Seidman, C. E., Seidman, J. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=12975413 publisherName HighWire Press title Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis. mimNumber 160760 referenceNumber 81 publisherAbbreviation HighWire pubmedID 12975413 source Heart 89: 1179-1185, 2003. authors Woo, A., Rakowski, H., Liew, J. C., Zhao, M.-S., Liew, C.-C., Parker, T. G., Zeller, M., Wigle, E. D., Sole, M. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2726733 publisherName HighWire Press title Characterization of human cardiac myosin heavy chain genes. mimNumber 160760 referenceNumber 82 publisherAbbreviation HighWire pubmedID 2726733 source Proc. Nat. Acad. Sci. 86: 3504-3508, 1989. Note: Erratum: Proc. Nat. Acad. Sci. 86: 7416-7417, 1989. authors Yamauchi-Takihara, K., Sole, M. J., Liew, J., Ing, D., Liew, C. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/1097-4598(200012)23:12<1876::AID-MUS13>3.0.CO;2-A publisherName John Wiley & Sons, Inc. title An autosomal dominant early adult-onset distal muscular dystrophy. mimNumber 160760 referenceNumber 83 publisherAbbreviation Wiley pubmedID 11102913 source Muscle Nerve 23: 1876-1879, 2000. authors Zimprich, F., Djamshidian, A., Hainfellner, J. A., Budka, H., Zeitlhofer, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ seeAlso Kurabayashi et al. (1988); Saez et al. (1987)

entryList

entry status live allelicVariantExists true epochCreated 889689600 geneMap geneSymbols HSF4, CTM, CTRCT5 sequenceID 11221 phenotypeMapList phenotypeMap phenotypeMimNumber 116800 mimNumber 602438 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 116200 phenotypeMappingKey 3 phenotype Cataract 5, multiple types chromosomeLocationStart 67197287 chromosomeSort 438 chromosomeSymbol 16 mimNumber 602438 geneInheritance None confidence C mappingMethod A, Fd geneName Heat-shock transcription factor 4 mouseMgiID MGI:1347058 mouseGeneSymbol Hsf4 computedCytoLocation 16q22.1 cytoLocation 16q21-q22.1 transcript uc002erl.2 chromosomeLocationEnd 67203847 chromosome 16 contributors Marla J. F. O'Neill - updated : 5/6/2013 Patricia A. Hartz - updated : 9/25/2007 Patricia A. Hartz - updated : 9/15/2006 Victor A. McKusick - updated : 6/19/2002 clinicalSynopsisExists false mimNumber 602438 allelicVariantList allelicVariant status live name CATARACT 5, LAMELLAR dbSnps rs121909048 text In affected members of a large Chinese family with lamellar cataract (CTRCT5; {116800}), {1:Bu et al. (2002)} identified a heterozygous 348T-C transition resulting in a leu115-to-pro (L115P) substitution in the DNA-binding domain of HSF4. The leucine residue specified by codon 115 is conserved among yeast, C. elegans, Drosophila, mouse, rat, and human and within the mostly conserved DNA-binding domains of the heat-shock factors. The autosomal dominant lamellar cataract in this family was described as a perinuclear-shaped lens opacity with a transparent embryonic nucleus. The earliest age of observed onset was 15 months. mutations HSF4, LEU115PRO number 1 clinvarAccessions RCV000007509;;1 status live name CATARACT 5, MULTIPLE TYPES dbSnps rs28937573 text In affected members of a large Danish family segregating cataract, originally reported by {3:Marner (1949)} and studied by {2:Eiberg et al. (1988)} with demonstration of linkage to haptoglobin on chromosome 16q (CTRCT5; {116800}), {1:Bu et al. (2002)} identified a heterozygous 362C-T transition in exon 3 of the HSF4 gene. The mutation was expected to result in substitution of a highly conserved arg120 residue by cysteine (R120C). The cataract in this Danish family occurred through 9 generations and was characterized by zonular stellate lens opacity with an anterior polar opacity and early childhood onset. mutations HSF4, ARG120CYS number 2 clinvarAccessions RCV000007510;;1 status live name CATARACT 5, LAMELLAR dbSnps rs121909049 text In a sporadic case of infantile lamellar cataract (CTRCT5; {116800}), {1:Bu et al. (2002)} identified a heterozygous C-to-A transversion in exon 1 of the HSF4 gene resulting in an ala20-to-asp (A20D) substitution in the DNA-binding region. This individual's parents did not have this mutation; thus, the mutation occurred de novo. mutations HSF4, ALA20ASP number 3 clinvarAccessions RCV000007511;;1 status live name CATARACT 5, LAMELLAR dbSnps rs121909050 text In a sporadic case of unilateral lamellar cataract (CTRCT5; {116800}), {1:Bu et al. (2002)} found a heterozygous ile87-to-val (I87V) substitution in the highly conserved DNA-binding domain of HSF4. The 46-year-old father carried the same mutation and showed a mild cataract with cortical water clefts and lamellar separation. mutations HSF4, ILE87VAL number 4 clinvarAccessions RCV000007512;;1 prefix * titles preferredTitle HEAT-SHOCK TRANSCRIPTION FACTOR 4; HSF4 textSectionList textSection textSectionTitle Cloning textSectionContent Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. Other members of the HSF family include HSF1 ({140580}) and HSF2 ({140581}). Using chicken HSF3 as a probe to screen a human HeLa cDNA library, {5:Nakai et al. (1997)} isolated an additional family member, termed HSF4 by the authors. Based on the low level of amino acid identity between chicken HSF3 and HSF4, {5:Nakai et al. (1997)} concluded that HSF4 is a novel member of the HSF family, rather than the human homolog of chicken HSF3. They reported that the HSF4 sequence encodes a 463-amino acid polypeptide. Northern blotting revealed that HSF4 is expressed as a 2.5-kb mRNA in the heart, skeletal muscle, and brain, and at much lower levels in some other tissues. {5:Nakai et al. (1997)} found that HSF4 bound specifically to the heat-shock response element but repressed, rather than activated, transcription. textSectionName cloning textSectionTitle Mapping textSectionContent {5:Nakai et al. (1997)} used fluorescence in situ hybridization to map the HSF4 gene to chromosome 16q21. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {1:Bu et al. (2002)} screened individuals of 3 Chinese families with cataract mapping to chromosome 16 (CTRCT5; {116800}) for mutations in the HSF4 gene and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregated with the disorder ({602438.0001}; {602438.0003}-{602438.0004}). They also discovered a missense mutation in HSF4 ({602438.0002}) in the extensive Danish family with Marner cataract. Thus it appears that HSF4 is critical to lens development. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Lens opacity 11 (Lop11) is an autosomal recessive mouse cataract mutation that arose spontaneously in the RIIIS/J strain. At 3 weeks of age, affected mice exhibit total cataracts with vacuoles. {6:Talamas et al. (2006)} mapped the Lop11 locus to mouse chromosome 8, and they identified an early transposable element in intron 9 of the Hsf4 gene. The insertion alters splicing and results in a truncated Hsf4 protein. {4:Mellersh et al. (2007)} found that 20 of 22 Boston terriers affected by early-onset hereditary cataract, which develops within the first year of life, were homozygous for an insertion in exon 9 of the Hsf4 gene that resulted in a premature stop codon and truncated protein. No mutations in the canine Hsf4 gene were associated with late-onset hereditary cataract, which develops between 3 and 6 years of age. textSectionName animalModel geneMapExists true editHistory alopez : 07/02/2014 carol : 5/6/2013 wwang : 7/21/2009 mgross : 9/27/2007 terry : 9/25/2007 wwang : 9/18/2006 terry : 9/15/2006 alopez : 6/24/2002 terry : 6/19/2002 terry : 7/24/1998 dholmes : 3/24/1998 dholmes : 3/18/1998 dateCreated Thu, 12 Mar 1998 03:00:00 EST creationDate Jennifer P. Macke : 3/12/1998 epochUpdated 1404284400 dateUpdated Wed, 02 Jul 2014 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1038/ng921 publisherName Nature Publishing Group title Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. mimNumber 602438 referenceNumber 1 publisherAbbreviation NPG pubmedID 12089525 source Nature Genet. 31: 276-278, 2002. authors Bu, L., Jin, Y., Shi, Y., Chu, R., Ban, A., Eiberg, H., Andres, L., Jiang, H., Zheng, G., Qian, M., Cui, B., Xia, Y., Liu, J., Hu, L., Zhao, G., Hayden, M. R., Kong, X. pubmedImages false publisherUrl http://www.nature.com title Marner's cataract (CAM) assigned to chromosome 16: linkage to haptoglobin. mimNumber 602438 referenceNumber 2 pubmedID 3233780 source Clin. Genet. 34: 272-275, 1988. authors Eiberg, H., Marner, E., Rosenberg, T., Mohr, J. pubmedImages false source Acta Ophthal. 27: 537-551, 1949. mimNumber 602438 authors Marner, E. title A family with eight generations of hereditary cataract. referenceNumber 3 articleUrl http://jhered.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17611257 publisherName HighWire Press title Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. mimNumber 602438 referenceNumber 4 publisherAbbreviation HighWire pubmedID 17611257 source J. Hered. 98: 531-533, 2007. authors Mellersh, C. S., Graves, K. T., McLaughlin, B., Ennis, R. B., Pettitt, L., Vaudin, M., Barnett, K. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=8972228 publisherName HighWire Press title HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. mimNumber 602438 referenceNumber 5 publisherAbbreviation HighWire pubmedID 8972228 source Molec. Cell. Biol. 17: 469-481, 1997. authors Nakai, A., Tanabe, M., Kawazoe, Y., Inazawa, J., Morimoto, R. I., Nagata, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(06)00053-X publisherName Elsevier Science title Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice. mimNumber 602438 referenceNumber 6 publisherAbbreviation ES pubmedID 16595169 source Genomics 88: 44-51, 2006. authors Talamas, E., Jackson, L., Koeberl, M., Jackson, T., McElwee, J. L., Hawes, N. L., Chang, B., Jablonski, M. M., Sidjanin, D. J. pubmedImages true publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:1347058 mgiHumanDisease false ncbiReferenceSequences 530423853,194394215,530423855,194440740,530423864,530423851,530423866,530423861,530423863,530423862,530423857,530423859 refSeqAccessionIDs NG_009294.1 dermAtlas false hprdIDs 03896 swissProtIDs Q9ULV5 zfinIDs ZDB-GENE-050306-18 uniGenes Hs.512156,Hs.710714 gtr true cmgGene false ensemblIDs ENSG00000102878,ENST00000264009 umlsIDs C1415752 genbankNucleotideSequences 79156470,164691378,164695986,14383448,14405598,19097861,71516170,1813425,157170549,46303369,194382361,80912029,24775338,5921134,29029228,5921132,148166732,511793144,194374382,19122264,152001138,148166731,110623528,123093993 geneTests true approvedGeneSymbols HSF4 geneIDs 3299 proteinSequences 119603489,119603491,119603490,119603492,157170550,1813426,194382362,296434534,5921135,5921133,100913211,194374383,100913209,152001139 nextGxDx false locusSpecificDBs http://www.LOVD.nl/HSF4;;HSF4 database at LOVD

entryList

entry status live allelicVariantExists true epochCreated 876466800 geneMap geneSymbols UCP3 sequenceID 8451 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 602044 phenotypeInheritance None phenotype {Obesity, severe, and type II diabetes} phenotypeMimNumber 601665 chromosomeLocationStart 73711325 chromosomeSort 625 chromosomeSymbol 11 mimNumber 602044 geneInheritance None confidence C mappingMethod REn, R, Psh geneName Uncoupling protein-3 mouseMgiID MGI:1099787 mouseGeneSymbol Ucp3 computedCytoLocation 11q13.4 cytoLocation 11q13 transcript uc001our.3 chromosomeLocationEnd 73720281 chromosome 11 contributors Patricia A. Hartz - updated : 8/2/2007 Anne M. Stumpf - updated : 4/1/2005 Marla J. F. O'Neill - updated : 3/4/2005 Ada Hamosh - updated : 12/1/2003 Patricia A. Hartz - updated : 11/15/2002 Ada Hamosh - updated : 1/2/2002 John A. Phillips, III - updated : 8/1/2001 Victor A. McKusick - updated : 9/28/2000 Ada Hamosh - updated : 7/27/2000 Joanna S. Amberger - updated : 5/25/2000 Victor A. McKusick - updated : 1/24/2000 Victor A. McKusick - updated : 10/17/1998 Victor A. McKusick - updated : 9/17/1998 Victor A. McKusick - updated : 1/19/1998 clinicalSynopsisExists false mimNumber 602044 allelicVariantList allelicVariant status live name UCP3 POLYMORPHISM G/A dbSnps rs2229707 text In a Gullah-speaking African American woman with severe obesity ({601665}) and type II diabetes ({125853}), {1:Argyropoulos et al. (1998)} found heterozygosity for a val102-to-ile (V102I) mutation of the UCP3 gene, located in the first cytosol-oriented extramembranous loop. Three overweight children in this family were found to be homozygous for the V102I polymorphism. The fourth child, a 9-year-old male with a body mass index (BMI) of 18.5, was heterozygous for the V102I polymorphism. No paternal sample was available but the father was presumed to be at least heterozygous for the V102I polymorphism. The polymorphism was not found in genomic DNA from 128 Caucasian Americans. However, examination of 280 African Americans revealed that 4% of individuals were homozygous and 28% heterozygous for the polymorphism. In the Mende tribe in Sierra Leone, 3% of the population was found to be homozygous A/A and 21% heterozygous G/A. mutations UCP3, 304G-A, VAL102ILE number 1 alternativeNames OBESITY, SEVERE, AND TYPE II DIABETES clinvarAccessions RCV000008013;;1;;;RCV000008012;;1 status live name OBESITY, SEVERE, AND TYPE II DIABETES dbSnps rs104894319 text In a 16-year-old with morbid obesity ({601665}) (BMI = 51.8) and type II diabetes ({125853}), {1:Argyropoulos et al. (1998)} found compound heterozygosity for a 427C-T transition in exon 4, resulting in the introduction of a premature stop codon at residue 143, arg143 to ter (R143X), in the third, matrix-oriented loop. In addition, the patient was heterozygous for a guanine to adenine polymorphism at the splice donor site of exon 6 (Ggt-Gat), resulting in loss of the splice junction and premature termination of the protein product in the sixth, matrix-oriented loop ({602044.0003}). A putative protein resulting from this mutation would be identical to that encoded by the short transcript of UCP3 mRNA. Pedigree analysis and DNA sequence determination of family members showed that the R143X mutation was transmitted to the compound heterozygous proband from the grandmother, through the mother, in typical mendelian fashion. The heterozygous polymorphism at the exon 6 splice donor junction (Ggt-Gat) was not detected in the maternal lineage and was most likely transmitted from the father, whose DNA was not available for analysis, but may have arisen as a new change. {1:Argyropoulos et al. (1998)} examined an additional 168 individuals comprising both African Americans and Caucasians for the 2 nucleotide changes. The R143X mutation was not detected in any other individual in either racial group. The exon 6 splice donor stop mutation, however, was detected in African-American subjects but not in Caucasians. An identical allele frequency (G, 90% and A, 10%) was found in Gullah-speaking African Americans and the Mende tribe. No homozygous subjects for the polymorphism (a/a) were detected in 287 Gullah-speaking African Americans and only 3 homozygotes were identified in 192 subjects of the Mende tribe. Haplotype analysis of 2 polymorphisms, V102I ({602044.0001}) and the exon 6 splice donor Ggt-Gat, showed that the 2 genotypes were independent. mutations UCP3, ARG143TER number 2 clinvarAccessions RCV000008014;;1 status live name UCP3 POLYMORPHISM, EXON 6 SPLICE DONOR JUNCTION text In a 16-year-old female with morbid obesity ({601665}), {1:Argyropoulos et al. (1998)} found compound heterozygosity for a polymorphism at the exon 6 splice donor junction (Ggt-Gat) and the R143X mutation ({602004.0002}). The rare R143X mutation was inherited in the maternal line; the splice site polymorphism was presumably transmitted from the father. The g-to-a transition at the splice donor site of exon 6 resulted in loss of the splice junction and truncation of the protein product at the first tga stop codon of the adjacent intron. Among unrelated individuals, {1:Argyropoulos et al. (1998)} found that heterozygotes for the exon 6 splice donor polymorphism had a 50% reduction in fat oxidation adjusted for lean body mass and a marked elevation in the nonprotein respiratory quotient, compared with wildtype subjects. No significant differences were found between heterozygotes and wildtype individuals for BMI, percentage of body fat, and resting energy expenditure adjusted for lean body mass. The same analyses performed for the V102I polymorphism ({602044.0001}) showed no significant differences between heterozygotes and wildtype individuals for any of the aforementioned quantitative traits. Nonetheless, the African American population studied had a high prevalence of obesity; therefore, the possibility that this could mask a potential effect of UCP3 mutations on BMI was also examined. Indeed, {1:Argyropoulos et al. (1998)} found that the frequency of the g/a heterozygous genotype was nearly twice as high (P = 0.04) in obese (30%) compared with lean (16%) individuals. mutations UCP3, IVS6, G-A, +1 number 3 alternativeNames OBESITY, SEVERE clinvarAccessions RCV000008015;;1;;;RCV000008016;;1 status live name OBESITY, SEVERE, AND TYPE II DIABETES dbSnps rs17848368 text {6:Brown et al. (1999)} identified a rare mutation in UCP3, arg70-to-trp, in a 15-year-old male of Chinese descent with severe obesity ({601665}) and type II diabetes ({125853}). Alignments showed that the mutated valine and arginine residues in V102I ({602044.0001}) and R70W are completely conserved in all known UCPs, including the plant UCP, suggesting that these residues may play an important functional role. {6:Brown et al. (1999)} expressed native human UCP3 mutations in yeast and showed complete loss on the uncoupling activity of UCP3 with R70W and no effect on this activity with V102I. mutations UCP3, ARG70TRP number 4 clinvarAccessions RCV000008017;;1 prefix * titles preferredTitle UNCOUPLING PROTEIN 3; UCP3 textSectionList textSection textSectionTitle Cloning textSectionContent {3:Boss et al. (1997)} and {21:Vidal-Puig et al. (1997)} described the cloning of UCP3 cDNAs. Both groups derived their clones from human skeletal muscle libraries, and both reported that UCP3 is approximately 57% and 73% identical to human UCP1 ({113730}) and UCP2 ({601693}), respectively. {3:Boss et al. (1997)} and {20:Solanes et al. (1997)} cloned a short isoform of UCP3 (UCP3S) containing 275 amino acids and a long isoform of UCP3 (UCP3L) containing 312 amino acids. UCP3S contains 3 mitochondrial energy-transfer-protein domains and 5 putative transmembrane domains, while UCP3L contains an additional 37 amino acids at its C terminus that encodes a putative transmembrane domain and a putative purine nucleotide-binding domain. {20:Solanes et al. (1997)} determined that UCP3S is generated when a cleavage and polyadenylation signal within the last intron prematurely terminates message elongation. {3:Boss et al. (1997)} used Northern blot analysis to show that in human tissue UCP3 is expressed as a 2.3-kb message in skeletal muscle and heart. In rat tissue, UCP3 transcripts were found in heart, brown adipose tissue, white adipose tissue, and skeletal muscle. textSectionName cloning textSectionTitle Gene Function textSectionContent {3:Boss et al. (1997)} examined UCP expression in cold-adapted rats and found that, unlike UCP1, the expression levels of UCP2 and UCP3 were not affected by cold. Nonetheless, the authors concluded that UCP3 may be involved in thermogenesis through the uncoupling of oxidative phosphorylation in skeletal muscle. {16:Millet et al. (1997)} observed an increase in the levels of UCP2 and UCP3 mRNA in skeletal muscle and adipose tissue from both lean and obese individuals undergoing fasting. They suggested that the increase indicates a role for these proteins in the metabolic adaptation to fasting. The similar induction of gene expression observed during fasting in lean and obese subjects show that there is no major alteration of UCP2 and UCP3 gene regulation in adipose tissue and skeletal muscle of obese subjects. UCP2 is widely expressed in human tissues, whereas UCP3 expression seems to be restricted to skeletal muscle, an important site of thermogenesis in humans. With the capacity to participate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene. {4:Bouchard et al. (1997)} demonstrated linkage between markers at the UCP2/UCP3 region with resting metabolic rate. This region is syntenic to a region of mouse chromosome 7 that has been linked to hyperinsulinemia and obesity ({11:Fleury et al., 1997}). {15:Liu et al. (1998)} and {14:Hinz et al. (1999)} showed that expression of UCP3 in yeast resulted in reduced cellular growth and a significant decrease in mitochondria membrane potential. {14:Hinz et al. (1999)} found that cellular respiration coupled to oxidative phosphorylation decreased, while cellular heat production increased. {15:Liu et al. (1998)} found that adenovirus-mediated leptin ({164160}) expression in obese ob/ob mice led to increased expression of Ucp3 in skeletal muscle, as well as significant weight loss. UCP1 diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose by catalyzing a regulated leak of protons across the inner membrane. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. {10:Echtay et al. (2002)} demonstrated that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2, and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. Superoxide-induced uncoupling correlates with the tissue expression of UCPs and appears in mitochondria from yeast expressing UCP1. Skeletal muscle mitochondria express only UCP3; therefore superoxide-induced uncoupling is absent in the skeletal muscle of UCP3 knockout mice. {10:Echtay et al. (2002)} concluded that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria. In 9 healthy male volunteers, {13:Hesselink et al. (2003)} measured the phosphocreatine resynthesis rate following intense anoxic contraction, which is a sensitive index of in vivo mitochondrial function, after 7 days on a low-fat diet and again after 7 days on a high-fat diet. The high-fat diet increased UCP3 protein content in muscle by 44% compared to the low-fat diet, but this increase in UCP3 was not associated with any changes in the rate of muscle phosphocreatine resynthesis during conditions of maximal flux through oxidative phosphorylation. {13:Hesselink et al. (2003)} concluded that the primary role of UCP3 in humans is not uncoupling. textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {20:Solanes et al. (1997)} determined that the UCP3 gene contains 7 exons and spans about 8.5 kb. The coding sequence uses exons 2 to 7 and spans about 5.25 kb. textSectionName geneStructure textSectionTitle Biochemical Features textSectionContent The observation that UCP3 is increased in situations where fatty acid entry into the mitochondria may exceed the beta-oxidation capacity suggested to {19:Russell et al. (2003}) that this protein may be involved in the outward translocation of fatty acid from the mitochondrial matrix. The authors performed biochemical and molecular tests using muscle from patients with riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency (MADD; {231680}), a lipid storage myopathy characterized by a decrease in fatty acid beta-oxidation capacity. The results demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see {157655}) and II (see {600857}), associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation. textSectionName biochemicalFeatures textSectionTitle Mapping textSectionContent By radiation hybrid analysis and PCR of P1 and BAC genomic clones, {20:Solanes et al. (1997)} mapped the UCP3 gene to chromosome 11q13, adjacent to the UCP2 gene. {23:Walder et al. (1998)} pointed out that the UCP2 and UCP3 genes constitute a cluster that maps to 11q13. {2:Boss et al. (1998)} described the genomic structure of the UCP3 gene and mapped the gene to 11q13 by somatic cell hybrid and radiation hybrid analysis. {18:Pecqueur et al. (1999)} determined that the UCP2 gene is located 7 kb downstream of the UCP3 gene. By PCR of mouse P1 and BAC clones, {20:Solanes et al. (1997)} mapped the mouse Ucp3 and Ucp2 genes to chromosome 7. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {1:Argyropoulos et al. (1998)} identified a missense polymorphism in exon 3 (V102I; {602044.0001}) of the UCP3 gene. A mutation introducing a stop codon in exon 4 (R143X; {602044.0002}) and a terminal polymorphism in the splice donor junction of exon 6 ({602044.0003}) were also identified in an individual who was morbidly obese and diabetic. Allele frequencies of the exon 3 and exon 6 splice junction polymorphisms were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians. Moreover, in exon 6 splice donor heterozygotes, basal fat oxidation rates were reduced by 50%, and the respiratory quotient was markedly increased compared with wildtype individuals, implicating a role for UCP3 in metabolic fuel partitioning. {5:Brown et al. (1999)} found that expression of native human UCP3 mutations in yeast showed complete loss (R70W; {602044.0004}), significant reduction (R143X; {602044.0002}), or no effect (V102I; {602044.0001} and +1G-A; {602044.0003}) on the uncoupling activity of UCP3. The authors concluded that certain mutations in UCP3 alter its functional impact on membrane potential, possibly conferring susceptibility to metabolic diseases. {9:Dalgaard et al. (2001)} tested whether variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-year follow-up among Danish subjects. Mutation screening of approximately 1 kb 5-prime upstream of the UCP3 gene revealed a C-to-T variant at -55 ({dbSNP rs1800849}). The frequency of this polymorphism was evaluated by restriction fragment length polymorphism analysis in 4 groups: 1) a group of 744 obese Danish men who at the draft board examinations had a BMI of at least 31 kg/m2; 2) a randomly selected control group consisting of 857 draftees; 3) 258 middle-aged subjects; and 4) 409 sixty-year-old subjects. The frequency of the T allele was 26.0% among the obese draftees and 26.9% in the control group. The authors concluded that this variant does not play a major role in the development of common obesity among Danish subjects. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {8:Clapham et al. (2000)} created transgenic mice that overexpress human UCP3 in skeletal muscle. UCP3 expression was driven by the human alpha-skeletal actin ({102610}) promoter, limiting expression to skeletal muscle. {8:Clapham et al. (2000)} bred 3 independent lines to homozygosity and selected a line of mice that had a 66-fold increase in UCP3 expression. These mice were hyperphagic but weighed less than their wildtype littermates. Magnetic resonance imaging (MRI) showed a striking reduction in adipose tissue mass. The mice also exhibited lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. {8:Clapham et al. (2000)} concluded that their data provided evidence that skeletal muscle UCP3 has the potential to influence metabolic rates and glucose homeostasis in the whole animal. {7:Choi et al. (2007)} showed that transgenic mice that overexpress human UCP3 in skeletal muscle were completely protected against the fat-induced defects and insulin resistance developed in wildtype mice fed a high-fat diet. Protection was associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKC-theta ({600448}) activity. Uncoupling protein-3 is a mitochondrial protein that can diminish the mitochondrial membrane potential. Levels of muscle UCP3 mRNA are increased by thyroid hormone and fasting. {12:Gong et al. (2000)} produced Ucp3 knockout mice to test the hypothesis that UCP3 influences metabolic efficiency and is a candidate obesity gene. The Ucp3 -/- mice had no detectable immunoreactive UCP3 by Western blot analysis. In mitochondria from the knockout mice, proton leak was greatly reduced in muscle, minimally reduced in brown fat, and not reduced at all in liver. These data suggested that UCP3 accounts for much of the proton leak in skeletal muscle. Despite the lack of UCP3, no consistent phenotypic abnormality was observed in the mice. They were not obese and had normal serum insulin, triglyceride, and leptin levels, with a tendency toward reduced free fatty acids and glucose. Knockout mice showed a normal circadian rhythm in body temperature and motor activity and had normal body temperature responses to fasting, stress, thyroid hormone, and cold exposure. The baseline metabolic rate and respiratory exchange ratio were the same in knockout and control mice, as were the effects of fasting, a beta-3 adrenergic agonist, and thyroid hormone on these parameters. The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp1 single knockout mice. The data suggested that Ucp3 is not a major determinant of metabolic rate but, rather, has other functions. In Ucp3 knockout mice, {22:Vidal-Puig et al. (2000)} found that skeletal muscle mitochondria lacking Ucp3 are more coupled (i.e., increased state 3/state 4 ratio), indicating that Ucp3 has uncoupling activity. In addition, production of reactive oxygen species was increased in mitochondria lacking Ucp3. Despite these effects on mitochondrial function, Ucp3 did not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. {17:Mills et al. (2003)} found that mice deficient in Ucp3 have a diminished thermogenic response to the drug MDMA, also known as 'ecstasy,' and did not die from a dose of 40 mg kg(-1), which killed 30% of wildtype littermates. Although the baseline temperature of Ucp3 -/- mice was indistinguishable from that of wildtype animals, Ucp3-deficient mice showed a significantly blunted rise in both skeletal muscle and rectal temperature following MDMA administration. {17:Mills et al. (2003)} concluded that UCP3 is important in MDMA-induced hyperthermia. textSectionName animalModel geneMapExists true editHistory joanna : 09/02/2008 wwang : 8/15/2007 terry : 8/2/2007 wwang : 9/19/2006 alopez : 4/1/2005 wwang : 3/10/2005 terry : 3/4/2005 alopez : 12/2/2003 terry : 12/1/2003 mgross : 11/15/2002 cwells : 8/8/2002 alopez : 1/3/2002 terry : 1/2/2002 mgross : 8/1/2001 mcapotos : 10/17/2000 mcapotos : 10/16/2000 terry : 10/6/2000 terry : 9/28/2000 alopez : 7/27/2000 terry : 6/1/2000 joanna : 5/25/2000 carol : 2/8/2000 carol : 2/3/2000 carol : 2/3/2000 carol : 1/31/2000 carol : 1/30/2000 terry : 1/24/2000 carol : 11/23/1998 carol : 10/28/1998 terry : 10/17/1998 terry : 9/17/1998 mark : 1/19/1998 mark : 1/19/1998 alopez : 10/22/1997 alopez : 10/10/1997 dateCreated Fri, 10 Oct 1997 03:00:00 EDT creationDate Jennifer P. Macke : 10/10/1997 epochUpdated 1220338800 dateUpdated Tue, 02 Sep 2008 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1172/JCI4115 publisherName Journal of Clinical Investigation title Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. mimNumber 602044 referenceNumber 1 publisherAbbreviation JCI pubmedID 9769326 source J. Clin. Invest. 102: 1345-1351, 1998. authors Argyropoulos, G., Brown, A. M., Willi, S. M., Zhu, J., He, Y., Reitman, M., Gevao, S. M., Spruill, I., Garvey, W. T. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(97)95135-1 publisherName Elsevier Science title Genomic structure of uncoupling protein-3 (UCP3) and its assignment to chromosome 11q13. mimNumber 602044 referenceNumber 2 publisherAbbreviation ES pubmedID 9480760 source Genomics 47: 425-426, 1998. authors Boss, O., Giacobino, J.-P., Muzzin, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(97)00384-0 publisherName Elsevier Science title Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. mimNumber 602044 referenceNumber 3 publisherAbbreviation ES pubmedID 9180264 source FEBS Lett. 408: 39-42, 1997. authors Boss, O., Samec, S., Paoloni-Giacobino, A., Rossier, C., Dulloo, A., Seydoux, J., Muzzin, P., Giacobino, J.-P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9302267 publisherName HighWire Press title Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. mimNumber 602044 referenceNumber 4 publisherAbbreviation HighWire pubmedID 9302267 source Hum. Molec. Genet. 6: 1887-1889, 1997. authors Bouchard, C., Perusse, L., Chagnon, Y. C., Warden, C., Ricquier, D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(99)01708-1 publisherName Elsevier Science title Endogenous mutations in human uncoupling protein 3 alter its functional properties. mimNumber 602044 referenceNumber 5 publisherAbbreviation ES pubmedID 10618503 source FEBS Lett. 464: 189-193, 1999. authors Brown, A. M., Dolan, J. W., Willi, S. M., Garvey, W. T., Argyropoulos, G. pubmedImages false publisherUrl http://www.elsevier.com/ source Hum. Mutat. 13: 508 only, 1999. Note: Full article online. mimNumber 602044 authors Brown, A. M., Willi, S. M., Argyropoulos, G., Garvey, W. T. title A novel missense mutation, R70W, in the human uncoupling protein 3 gene in a family with type 2 diabetes. (Abstract) referenceNumber 6 articleUrl http://dx.doi.org/10.1172/JCI13579 publisherName Journal of Clinical Investigation title Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. mimNumber 602044 referenceNumber 7 publisherAbbreviation JCI pubmedID 17571165 source J. Clin. Invest. 117: 1995-2003, 2007. authors Choi, C. S., Fillmore, J. J., Kim, J. K., Liu, Z.-X., Kim, S., Collier, E. F., Kulkarni, A., Distefano, A., Hwang, Y.-J., Kahn, M., Chen, Y., Yu, C., Moore, I. K., Reznick, R. M., Higashimori, T., Shulman, G. I. pubmedImages true publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1038/35019082 publisherName Nature Publishing Group title Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. mimNumber 602044 referenceNumber 8 publisherAbbreviation NPG pubmedID 10935638 source Nature 406: 415-418, 2000. authors Clapham, J. C., Arch, J. R. S., Chapman, H., Haynes, A., Lister, C., Moore, G. B. T., Piercy, V., Carter, S. A., Lehner, I., Smith, S. A., Beeley, L. J., Godden, R. J., {and 15 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11238538 publisherName HighWire Press title A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population. mimNumber 602044 referenceNumber 9 publisherAbbreviation HighWire pubmedID 11238538 source J. Clin. Endocr. Metab. 86: 1398-1402, 2001. authors Dalgaard, L. T., Sorensen, T. I. A., Drivsholm, T., Borch-Johnsen, K., Andersen, T., Hansen, T., Pedersen, O. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/415096a publisherName Nature Publishing Group title Superoxide activates mitochondrial uncoupling proteins. mimNumber 602044 referenceNumber 10 publisherAbbreviation NPG pubmedID 11780125 source Nature 415: 96-99, 2002. authors Echtay, K. S., Roussel, D., St-Pierre, J., Jekabsons, M. B., Cadenas, S., Stuart, J. A., Harper, J. A., Roebuck, S. J., Morrison, A., Pickering, S., Clapham, J. C., Brand, M. D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0397-269 publisherName Nature Publishing Group title Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. mimNumber 602044 referenceNumber 11 publisherAbbreviation NPG pubmedID 9054939 source Nature Genet. 15: 269-272, 1997. authors Fleury, C., Neverova, M., Collins, S., Raimbault, S., Champigny, O., Levi-Meyrueis, C., Bouillaud, F., Seldin, M. F., Surwit, R. S., Ricquier, D., Warden, C. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10748195 publisherName HighWire Press title Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. mimNumber 602044 referenceNumber 12 publisherAbbreviation HighWire pubmedID 10748195 source J. Biol. Chem. 275: 16251-16257, 2000. authors Gong, D.-W., Monemdjou, S., Gavrilova, O., Leon, L. R., Marcus-Samuels, B., Chou, C. J., Everett, C., Kozak, L. P., Li, C., Deng, C., Harper, M.-E., Reitman, M. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI16653 publisherName Journal of Clinical Investigation title Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. mimNumber 602044 referenceNumber 13 publisherAbbreviation JCI pubmedID 12588886 source J. Clin. Invest. 111: 479-486, 2003. authors Hesselink, M. K. C., Greenhaff, P. L., Constantin-Teodosiu, D., Hultman, E., Saris, W. H. M., Nieuwlaat, R., Schaart, G., Kornips, E., Schrauwen, P. pubmedImages true publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(99)00331-2 publisherName Elsevier Science title Recombinant human uncoupling protein-3 increases thermogenesis in yeast cells. mimNumber 602044 referenceNumber 14 publisherAbbreviation ES pubmedID 10217410 source FEBS Lett. 448: 57-61, 1999. authors Hinz, W., Faller, B., Gruninger, S., Gazzotti, P., Chiesi, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0378-1119(97)00596-9 publisherName Elsevier Science title Uncoupling protein-3: a muscle-specific gene upregulated by leptin in ob/ob mice. mimNumber 602044 referenceNumber 15 publisherAbbreviation ES pubmedID 9511737 source Gene 207: 1-7, 1998. authors Liu, Q., Bai, C., Chen, F., Wang, R., MacDonald, T., Gu, M., Zhang, Q., Morsy, M. A., Caskey, C. T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI119811 publisherName Journal of Clinical Investigation title Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. mimNumber 602044 referenceNumber 16 publisherAbbreviation JCI pubmedID 9389729 source J. Clin. Invest. 100: 2665-2670, 1997. authors Millet, L., Vidal, H., Andreelli, F., Larrouy, D., Riou, J.-P., Ricquier, D., Laville, M., Langin, D. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1038/426403a publisherName Nature Publishing Group title Uncoupling the agony from ecstasy: deactivating a single protein could prevent one of the drug's most dangerous effects. mimNumber 602044 referenceNumber 17 publisherAbbreviation NPG pubmedID 14647371 source Nature 426: 403-404, 2003. authors Mills, E. M., Banks, M. L., Sprague, J. E., Finkel, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(98)90146-2 publisherName Elsevier Science title Functional organization of the human uncoupling protein-2 gene and juxtaposition to the uncoupling protein-3 gene. mimNumber 602044 referenceNumber 18 publisherAbbreviation ES pubmedID 10082652 source Biochem. Biophys. Res. Commun. 255: 40-46, 1999. authors Pecqueur, C., Cassard-Doulcier, A.-M., Raimbault, S., Miroux, B., Fleury, C., Gelly, C., Bouillaud, F., Ricquier, D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=14671191 publisherName HighWire Press title Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3. mimNumber 602044 referenceNumber 19 publisherAbbreviation HighWire pubmedID 14671191 source J. Clin. Endocr. Metab. 88: 5921-5926, 2003. authors Russell, A. P., Schrauwen, P., Somm, E., Gastaldi, G., Hesselink, M. K. C., Schaart, G., Kornips, E., Lo, S. K., Bufano, D., Giacobino, J.-P., Muzzin, P., Ceccon, M., Angelini, C., Vergani, L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9325252 publisherName HighWire Press title The human uncoupling protein-3 gene: genomic structure, chromosomal localization, and genetic basis for short and long form transcripts. mimNumber 602044 referenceNumber 20 publisherAbbreviation HighWire pubmedID 9325252 source J. Biol. Chem. 272: 25433-25436, 1997. authors Solanes, G., Vidal-Puig, A., Grujic, D., Flier, J. S., Lowell, B. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(97)96740-1 publisherName Elsevier Science title UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. mimNumber 602044 referenceNumber 21 publisherAbbreviation ES pubmedID 9196039 source Biochem. Biophys. Res. Commun. 235: 79-82, 1997. authors Vidal-Puig, A., Solanes, G., Grujic, D., Flier, J. S., Lowell, B. B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10748196 publisherName HighWire Press title Energy metabolism in uncoupling protein 3 gene knockout mice. mimNumber 602044 referenceNumber 22 publisherAbbreviation HighWire pubmedID 10748196 source J. Biol. Chem. 275: 16258-16266, 2000. authors Vidal-Puig, A. J., Grujic, D., Zhang, C.-Y., Hagen, T., Boss, O., Ido, Y., Szczepanik, A., Wade, J., Mootha, V., Cortright, R., Muoio, D. M., Lowell, B. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9700198 publisherName HighWire Press title Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima Indians. mimNumber 602044 referenceNumber 23 publisherAbbreviation HighWire pubmedID 9700198 source Hum. Molec. Genet. 7: 1431-1435, 1998. authors Walder, K., Norman, R. A., Hanson, R. L., Schrauwen, P., Neverova, M., Jenkinson, C. P., Easlick, J., Warden, C. H., Pecqueur, C., Raimbault, S., Ricquier, D., Harper, M., Silver, K., Shuldiner, A. R., Solanes, G., Lowell, B. B., Chung, W. K., Leibel, R. L., Pratley, R., Ravussin, E. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:1099787 mgiHumanDisease false ncbiReferenceSequences 215272355,215272349 refSeqAccessionIDs NG_011515.1 dermAtlas false hprdIDs 03623 swissProtIDs P55916 zfinIDs ZDB-GENE-040426-1317 uniGenes Hs.101337,Hs.621879 gtr true cmgGene false ensemblIDs ENSG00000175564,ENST00000314032 umlsIDs C1421315 genbankNucleotideSequences 21751337,6701732,3176758,2522401,2183017,2440012,164690745,14250000,4836644,71517006,158254691,2183020,2641639,511800270,20334343,9937094,158257209,23285083,2198812,81226410,148174666 geneTests true approvedGeneSymbols UCP3 geneIDs 7352 proteinSequences 119595331,119595332,2522403,119595333,3176760,2440013,14250001,158254692,2183018,2183021,9937095,13259546,193787389,158257210,2497983,4507807,2198813 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 825494400 geneMap geneSymbols PMP22, CMT1A, CMT1E, DSS sequenceID 11591 phenotypeMapList phenotypeMap phenotypeMimNumber 118220 mimNumber 601097 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, type 1A phenotypeMimNumber 118300 mimNumber 601097 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Charcot-Marie-Tooth disease, type 1E phenotypeMimNumber 145900 mimNumber 601097 phenotypeInheritance Autosomal recessive; Autosomal dominant phenotypicSeriesMimNumber 118220 phenotypeMappingKey 3 phenotype Dejerine-Sottas disease phenotypeMappingKey 3 mimNumber 601097 phenotypeInheritance ?Autosomal dominant phenotype Neuropathy, inflammatory demyelinating phenotypeMimNumber 139393 phenotypeMappingKey 3 mimNumber 601097 phenotypeInheritance Autosomal dominant phenotype Neuropathy, recurrent, with pressure palsies phenotypeMimNumber 162500 phenotypeMappingKey 3 mimNumber 601097 phenotypeInheritance Autosomal dominant phenotype Roussy-Levy syndrome phenotypeMimNumber 180800 chromosomeLocationStart 15133093 chromosomeSort 191 chromosomeSymbol 17 mimNumber 601097 geneInheritance None confidence C mappingMethod Fd, D, A geneName Peripheral myelin protein-22 mouseMgiID MGI:97631 references Lupski (1991); Timmerman (1992) mouseGeneSymbol Pmp22 computedCytoLocation 17p12 cytoLocation 17p11.2 transcript uc002goj.3 chromosomeLocationEnd 15168673 chromosome 17 contributors Cassandra L. Kniffin - updated : 4/23/2014 Cassandra L. Kniffin - updated : 7/1/2013 Cassandra L. Kniffin - updated : 9/25/2012 Cassandra L. Kniffin - updated : 4/11/2012 Cassandra L. Kniffin - updated : 7/12/2010 Cassandra L. Kniffin - updated : 1/25/2010 Ada Hamosh - updated : 9/4/2009 Cassandra L. Kniffin - updated : 3/3/2009 Cassandra L. Kniffin - updated : 4/1/2008 Cassandra L. Kniffin - updated : 7/17/2006 Cassandra L. Kniffin - updated : 4/17/2006 Cassandra L. Kniffin - updated : 7/12/2005 Cassandra L. Kniffin - updated : 10/25/2004 Victor A. McKusick - updated : 11/17/2003 Cassandra L. Kniffin - updated : 10/1/2003 Cassandra L. Kniffin - updated : 9/17/2003 Cassandra L. Kniffin - updated : 8/11/2003 Cassandra L. Kniffin - updated : 5/1/2003 Cassandra L. Kniffin - reorganized : 4/28/2003 Cassandra L. Kniffin - updated : 4/25/2003 Victor A. McKusick - updated : 4/16/2002 Victor A. McKusick - updated : 1/31/2002 Ada Hamosh - updated : 1/10/2001 Victor A. McKusick - updated : 12/19/2000 George E. Tiller - updated : 9/22/2000 Ada Hamosh - updated : 6/14/1999 Victor A. McKusick - updated : 6/14/1999 Victor A. McKusick - updated : 4/2/1999 Michael J. Wright - updated : 2/10/1999 Victor A. McKusick - updated : 2/4/1999 Victor A. McKusick - updated : 1/12/1999 Orest Hurko - updated : 9/23/1998 Victor A. McKusick - updated : 5/15/1998 Victor A. McKusick - updated : 6/23/1997 Victor A. McKusick - updated : 2/7/1997 Moyra Smith - updated : 6/18/1996 Orest Hurko - updated : 5/8/1996 Orest Hurko - updated : 3/26/1996 Orest Hurko - updated : 3/6/1996 clinicalSynopsisExists false mimNumber 601097 allelicVariantList allelicVariant status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A text {40:Lupski et al. (1991)} found a DNA duplication on chromosome 17p as the apparent basis of CMT1A ({118220}). They showed complete linkage and association of this duplication in 7 multigenerational CMT1A pedigrees and in several isolated, unrelated patients. Pulsed field gel electrophoresis of genomic DNA from CMT1 patients of different ethnic origins showed a novel SacII fragment of 500 kb, and this fragment showed mendelian inheritance. The duplication was also directly visualized by 2-color FISH in interphase nuclei. {40:Lupski et al. (1991)} found that a severely affected person, the product of a first-cousin marriage ({27:Killian and Kloepfer, 1979}), was homozygous for the duplication. Onset was before age 1 year and reduction in motor nerve conduction velocity was severe. A less severely affected sister was heterozygous for the duplication. The finding implicated a local DNA duplication, a segmental trisomy, as a novel mechanism for an autosomal dominant human disease. The classic example of a DNA duplication is the Bar locus in Drosophila melanogaster as described by {7:Bridges (1936)}. {39:Lupski et al. (1991)} noted that failure to recognize the molecular duplication could lead to misinterpretation of marker genotypes for affected persons with identification of false recombinance and incorrect localization of the disease locus. The duplication was likewise demonstrated by {62:Raeymaekers et al. (1991)} who, like {40:Lupski et al. (1991)}, concluded that the duplication is probably the mutation responsible for the disease. The duplication was demonstrated in locus D17S122 (probe VAW409R3). Using pulsed field gel electrophoresis analysis, {21:Hoogendijk et al. (1991)} estimated the minimal size of the duplicated region in CMT1A patients to be 1,100 kb. While trying to determine the size of the chromosome 17 duplication, {63:Raeymaekers et al. (1992)} showed that on the genetic map the duplicated markers span a minimal distance of 10 cM, while on the physical map they are present in the same NotI restriction fragment of 1,150 kb. The discrepancy between the genetic and physical map distances suggests that the 17p11.2 region is highly prone to recombination. The authors suggested that the high recombination rate may be a contributing factor to the genetic instability of the region. {88:Valentijn et al. (1992)} used 2-color fluorescence in situ hybridization (FISH) on interphase nuclei of fibroblasts to demonstrate that the duplication is a direct tandem repeat: they observed red-green for the normal chromosome and red-green-red-green for the chromosome with the duplication; in none of the nuclei analyzed was the order red-green-green-red or green-red-red-green, compatible with an inverted repeat. The authors suggested that those affected families in which there is no duplication of the PMP22 gene likely represent intragenic mutations comparable to those in the Trembler mouse. {20:Hoogendijk et al. (1992)} found the chromosome 17 duplication as a de novo mutation in 9 of 10 sporadic patients with HMSN I. During a population survey of CMT1 in south Wales, {42:MacMillan et al. (1992)} found duplication of locus D17S122, recognized by a DNA probe that detects an MspI polymorphism, in 10 of 11 families selected only by clinical criteria. Trisomy for this chromosome region is demonstrated either by the presence of 3 alleles or a dosage effect when only 2 of the alleles are present. The 1 family without trisomy did not differ in type or severity of disease from the other families. {41:Lupski et al. (1992)} described a patient with a cytogenetically visible duplication, dup(17)(p11.2p12). Molecular analysis demonstrated that this patient had duplications of all the DNA markers duplicated in other cases of CMT1A as well as of markers both proximal and distal to the CMT1A duplication. {86:Upadhyaya et al. (1993)} reported another instance of a microscopically visible duplication of 17p12-p11.2 in association with CMT1A. {91:Wise et al. (1993)} used 3 molecular methods to search for the CMT1A DNA duplication in 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiologic methods. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiologic studies consistent with CMT type 1. The CMT1A duplication was detected as a de novo event in 2 CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment by pulsed field gel electrophoresis. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, {91:Wise et al. (1993)} concluded that a molecular test for the CMT1A DNA duplication is useful in the differential diagnosis of patients with peripheral neuropathies. In a 2-year-old boy with severe demyelinating CMT, {48:Meggouh et al. (2005)} identified compound heterozygosity for 2 mutations: the PMP22 duplication and a mutation in the LITAF gene (G112S; {603795.0001}), which causes CMT1C ({601098}). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. {48:Meggouh et al. (2005)} concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband. In 3 members of a 4-generation family with Roussy-Levy syndrome ({180800}), {3:Auer-Grumbach et al. (1998}) identified the CMT1A PMP22 duplication. {49:Miltenberger-Miltenyi et al. (2009)} identified the CMT1A PMP22 1.4-Mb duplication in 79 (31.6%) of 250 unrelated Austrian patients with CMT. mutations PMP22, 1.4-MB DUP number 1 alternativeNames ROUSSY-LEVY SYNDROME, INCLUDED clinvarAccessions RCV000008939;;1;;;RCV000008938;;2 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A dbSnps rs104894617 text {87:Valentijn et al. (1992)} demonstrated a mutation leading to the substitution of proline for leucine in the first putative transmembrane domain of PMP22 as the cause of CMT1A ({118220}) in a Dutch kindred. A T-to-C transition at position 96 was responsible for the leu16-to-pro substitution. The identical mutation had been identified in the 'Trembler-J' mouse, a homolog of the human disease. Thus, either duplication or point mutation in the PMP22 gene can result in CMT1A. {22:Hoogendijk et al. (1993)} had previously shown that the clinical disorder in this family was tightly linked to a probe on 17p11.2. The histopathologic abnormalities in nerve biopsies of patients from this family were unusually severe ({13:Gabreels-Festen et al., 1992}). {22:Hoogendijk et al. (1993)} commented that, according to the clinical, neurophysiologic, and morphologic criteria used by some investigators, most of the patients in this family would individually be given a diagnosis of HMSN I (Dejerine-Sottas disease; {145900}). mutations PMP22, LEU16PRO number 2 clinvarAccessions RCV000008940;;2 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A dbSnps rs104894618 text {68:Roa et al. (1993)} analyzed DNA samples from 32 unrelated CMT1A ({118220}) patients with type 1 CMT who did not have the 1.5-Mb tandem duplication in 17p12-p11.2. Searching for mutations within the PMP22 region, they found in 1 family a C-to-G transversion, corresponding to the substitution of cysteine for serine in the 79th codon (S79C) of PMP22. The substitution occurred in the second putative transmembrane domain of PMP22. mutations PMP22, SER79CYS number 3 clinvarAccessions RCV000008941;;1 status live name NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES text Using DNA markers, {8:Chance et al. (1993)} demonstrated a large interstitial deletion in distal 17p11.2 in persons with hereditary neuropathy with liability to pressure palsies ({162500}), also called 'bulb diggers' palsy,' in 3 unrelated kindreds. In 1 pedigree, de novo genesis of the deletion was documented. The deletion spanned approximately 1.5 Mb and included all markers that were known to be duplicated in CMT1A. The deleted region appeared uniform in all pedigrees and included the PMP22 gene. Since the breakpoints in hereditary neuropathy with pressure palsy and CMT1A map to the same intervals in 17p11.2, one can conclude that these genetic disorders may be the result of reciprocal products of unequal crossingover. {38:Lorenzetti et al. (1995)} studied 9 unrelated Italian families with HNPP identified on the basis of clinical, electrophysiologic, and histologic evaluations. In all 9 families, Southern blot analysis indicated deletion of 1 copy of the probe used in the HNPP patients. Deletion was also indicated by typing with a polymorphic (CA)n repeat and with 3 RFLPs, all known to map within the deleted region. These findings suggested that a 1.5-Mb deletion is the most common mutation associated with HNPP. To evaluate the frequency of 17p11.2 deletion involving a rearrangement in the CMT1A-REP (the 2 homologous sequences flanking the 1.5-Mb CMT1A/HNPP monomer unit), {33:LeGuern et al. (1995)} analyzed EcoRI-digested DNA from 30 unrelated patients by hybridization with appropriate probes. In this large series, the HNPP phenotype, determined by clinical and electrophysiologic criteria, was associated with a 17p11.2 deletion in 90% (27/30) of the patients. The 3 patients who did not carry the CMT1A/HNPP monomer unit deletion may have had mutations in the PMP22 gene or possibly in the P-zero gene ({159440}). Inflammatory demyelinating polyneuropathy (see {139393}), a putative autoimmune disorder, presents in an acute (AIDP; Guillain-Barre syndrome) or chronic form (CIDP). {30:Korn-Lubetzki et al. (2002)} described a father and 2 daughters of Jewish Kurdish origin who developed inflammatory demyelinating polyneuropathy within 10 years of each other. DNA analysis in the father and 1 daughter who was available for study revealed a 1.5-kb deletion of the PMP22 gene. The father presented at the age of 50 years with asymmetric distal involvement of the legs and right hand following surgery. Demyelination was demonstrated by sural nerve biopsy. Each of his 2 daughters presented at the age of 24 years with asymmetric distal involvement of the legs and left hand. Neither the father nor the daughters had evidence of preceding trauma or compression. {2:Al-Thihli et al. (2008)} reported a 7-year-old boy with autosomal recessive Dejerine-Sottas disease ({145900}) associated with compound heterozygous deletions in the PMP2 gene: the common 1.5-Mb deletion and a deletion encompassing exons 2 and 3 ({601097.0020}). The nonconsanguineous parents were each heterozygous for a deletion and showed an HNPP phenotype. {2:Al-Thihli et al. (2008)} used multiplex ligation probe-dependent amplification (MLPA) to determine the breakpoints of the deletions. The 1.5-Mb deletion, which the authors stated was the 'typical' HNPP-associated deletion, included the neighboring TEKT3 ({612683}) and COX10 ({602125}) genes. {72:Saporta et al. (2011)} reported a 7-year-old boy, born of consanguineous parents, with a homozygous 1.1-Mb deletion of chromosome 17p including all 5 exons of the PMP22 gene, the TEKT3 gene, and the FLJ gene, but not the COX10 gene. The deletion was identified by MLPA. Each unaffected parent was heterozygous for the deletion and had electrophysiologic features of HNPP. The boy was first noted to have hypotonia at age 4 months, and later showed delayed walking with an unsteady sensory ataxic gait requiring a walker. He had distal weakness of the hands and distal sensory impairment with areflexia. He also had bilateral facial weakness, mild ptosis, and mild hammertoes, but no pes cavus. Interestingly, he had no atrophy or weakness of the muscles in the limbs, suggesting normal motor function, although electrophysiologic studies showed slowed peroneal motor conduction velocities. Sural nerve sensory responses were unobtainable. Skin biopsy showed a reduction in myelinated fiber density, with noncompact myelin, axonal loss, and redundancy of the basal lamina around or near Schwann cells. {72:Saporta et al. (2011)} noted that this was the first reported patient with complete homozygous deletion of the PMP22 gene. The authors suggested that lack of PMP22's normal differential expression in motor and sensory axons during development contributed to the patient's phenotype of predominantly large fiber sensory loss with nonlength-dependent mild motor impairment. mutations PMP22, 1.1- to 1.5-MB DEL number 4 alternativeNames POLYNEUROPATHY, INFLAMMATORY DEMYELINATING, INCLUDED;; DEJERINE-SOTTAS SYNDROME, AUTOSOMAL RECESSIVE, INCLUDED clinvarAccessions RCV000008943;;1;;;RCV000008942;;1;;;RCV000008944;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A, AUTOSOMAL RECESSIVE dbSnps rs104894619 text {67:Roa et al. (1993)} identified a severely affected CMT1A ({118220}) patient who was compound heterozygous for 2 mutations in the PMP22 gene: a 353C-T transition, resulting in a thr118-to-met (T118M) substitution, and a 1.5-Mb deletion ({601097.0004}). The findings were consistent with autosomal recessive inheritance. A son heterozygous for the T118M mutation had no signs of neuropathy, while 2 other sons heterozygous for the 1.5-Mb deletion had hereditary neuropathy with liability to pressure palsies (HNPP; {162500}). The deletion was demonstrated by FISH in the severely affected patient and in her affected sons. {4:Bathke et al. (1996)} reported a man with CMT1A who was compound heterozygous for T118M and a 1.5-Mb deletion in the PMP22 gene. His unaffected mother was heterozygous for the T118M substitution. The T118M substitution was not identified in 104 healthy control individuals. {52:Nelis et al. (1997)} presented evidence suggesting that the T118M substitution is not pathogenic. Although they identified heterozygosity for T118M in a single patient with CMT1, the patient's unaffected father also carried the substitution. The T118M substitution was also identified in the unaffected father of another family with CMT1, whereas the affected patient in that family did not have the substitution. The T118M substitution was also identified in the heterozygous state in 10 of 262 controls from northern Sweden, yielding an allele frequency of 1.9%. {54:Niedrist et al. (2009)} identified a T118M substitution in cis with a truncating PMP22 mutation ({601097.0021}) in a 20-year-old man with severe CMT1A. The phenotype was attributed to the truncating mutation because the truncated protein would not contain the downstream T118M substitution. Analysis of the parents showed that the clinically unaffected father was heterozygous for the T118M substitution, which suggested that the T118M substitution may not be pathogenic, although electrophysiologic studies were not performed on the father. {75:Shy et al. (2006)} reported 3 unrelated individuals with a mild demyelinating neuropathy similar to HNPP who were heterozygous for the T118M substitution. Two members of a fourth kindred with mild CMT1A and electrophysiologic features of HNPP had the T118M substitution and a duplication of the PMP22 gene ({601097.0001}). In a fifth family, a child with early-onset severe axonal neuropathy was found to be homozygous for the T118M mutation. Although she had severe denervation, she did not have overt demyelination. Her unaffected parents, who had electrophysiologic features consistent with HNPP, were both heterozygous for T118M. {75:Shy et al. (2006)} concluded that the T118M substitution is a pathogenic mutation resulting in a partial loss of protein function. The authors suggested that the corresponding phenotypes are due to a PMP22 dosage effect; T118M may thus act as a dominant allele with reduced penetrance. mutations PMP22, THR118MET number 5 alternativeNames NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES, INCLUDED clinvarAccessions RCV000008945;;1;;;RCV000008946;;2;;;RCV000032119;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT dbSnps rs104894620 text Dejerine-Sottas syndrome ({145900}) is characterized by hypertrophic, demyelinating neuropathy. Clinical symptoms are similar to but more severe than those of Charcot-Marie-Tooth disease type 1A ({118220}). By mutation analysis of the PMP22 coding region in 2 unrelated Dejerine-Sottas patients, {66:Roa et al. (1993)} identified individual missense point mutations present in the heterozygous state. In 1 family, both parents were negative for the mutations, suggesting that it was de novo in origin. One patient had a T-to-A transversion predicting a met69-to-lys substitution, whereas the other had a C-to-T transition predicting a ser72-to-leu substitution. The patient with the met69-to-lys substitution had no detectable abnormality at birth but did not begin walking until age 15 months and did so with an abnormal gait. Bilateral pes cavus was noted at age 6, and delayed nerve conduction velocity in the left ulnar nerve was measured at age 7. By age 18, she had severe lower limb weakness necessitating the use of a wheelchair and severe distal sensory loss in all 4 limbs. No other family member was known to be similarly affected. Electron microscopy of sural nerve biopsy demonstrated hypertrophy of the nerve with marked loss or abnormality of myelinated fibers. mutations PMP22, MET69LYS number 6 clinvarAccessions RCV000008947;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT dbSnps rs104894621 text The patient in whom {66:Roa et al. (1993)} demonstrated the ser72-to-leu substitution was an 8-year-old male who had severe hypotonia and weakness at birth, delayed motor milestones with normal speech development, and gradual improvement in motor abilities. He walked with the aid of leg braces and a walker at 7 years of age. There was marked distal atrophy of the lower limbs, mild weakness of the intrinsic hand muscles, and absent deep tendon reflexes in all 4 limbs. Sensory examination showed distal decrease in sensation to pinprick and temperature in all limbs. Motor nerve conduction velocity and sural nerve biopsy were typical of Dejerine-Sottas syndrome ({145900}). The mother of the patient, who died at 30 years of age from respiratory failure, had a history of similar neuromuscular problems. DNA was not available from that patient. {25:Ionasescu et al. (1996)} found the same mutation in a patient with Dejerine-Sottas syndrome who also showed sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness. The ser72l-to-leu mutation had occurred de novo. The authors stated that nystagmus and peripheral facial nerve weakness had not previously been reported in Dejerine-Sottas syndrome. {44:Marques et al. (1998)} detected the same mutation in a 7-year-old girl with Dejerine-Sottas syndrome. The authors proposed that ser72 may be a hotspot for mutation. mutations PMP22, SER72LEU number 7 clinvarAccessions RCV000008948;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT dbSnps rs104894622 text {89:Valentijn et al. (1995)} identified a de novo mutation in the PMP22 gene of a patient with Dejerine-Sottas neuropathy ({145900}). Single-strand conformation analysis of PCR-amplified DNA fragments showed an additional fragment for exon 1 in the patient, which was absent in the unaffected parents. Sequence analysis showed a de novo C-to-A transversion at nucleotide 85 that resulted in an amino acid substitution his12-to-gln in the first transmembrane domain of PMP22. The patient had been described as case 13 by {57:Ouvrier et al. (1987)}. At 4 years of age, the child's height and weight were below the third centile. There was generalized weakness of mild to moderate severity. All tendon reflexes were absent, except the triceps. Peripheral nerves were clinically enlarged. There was moderate truncal ataxia. Sensation was normal, except for mild loss of vibration sensation and diminished 2-point discrimination on the feet. Sensory action potentials could not be recorded from the right median or sural nerves. Motor nerve conduction velocity in the median nerve was 7 m/sec. Sural nerve biopsy at 2 years of age had shown reduced density of myelinated fibers, and all fibers were thinly myelinated and frequently surrounded by onion bulbs. mutations PMP22, HIS12GLN number 8 clinvarAccessions RCV000008949;;1 status live name NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES dbSnps rs587776691 text {53:Nicholson et al. (1994)} used SSCP analysis to study the PMP22 gene in an Australian family that was transmitting hereditary neuropathy with liability to pressure palsies ({162500}) but did not show a 1.5-Mb deletion ({118220.0004}). The affected individuals were heterozygous for a 2-bp deletion (207delTC) in exon 1 of the PMP22 gene, resulting in a frameshift at ser7 and premature stop at codon 36. The authors stated that this mutation provided further evidence that absence of one copy of the PMP22 gene is sufficient to cause liability to pressure palsies. {34:Li et al. (2007)} found a 24% reduction of PMP22 levels in myelinated fibers from dermal nerves of affected members of the HNPP family reported by {53:Nicholson et al. (1994)}. Electrophysiologic studies showed a pattern similar to HNPP resulting from the classic PMP22 deletion, with accentuated distal slowing occurring at sites subject to nerve compression. Three patients older than age 65 years had clinical and electrophysiologic evidence of length-dependent axonal loss. {34:Li et al. (2007)} concluded that the phenotype of HNPP due to a PMP22 truncating mutation (which they referred to as a leu7fs) is indistinguishable from that due to the PMP22 1.5-Mb deletion. mutations PMP22, 2-BP DEL, 207TC number 9 clinvarAccessions RCV000008950;;1 status live name CHARCOT-MARIE-TOOTH DISEASE AND DEAFNESS dbSnps rs104894623 text In a family with progressive features of Charcot-Marie-Tooth disease and deafness ({118300}) originally reported by {31:Kousseff et al. (1982)}, {32:Kovach et al. (1999)} found linkage to markers on 17p12-p11.2. Direct sequencing of the PMP22 gene detected a unique G-to-C transversion at nucleotide 248 in coding exon 3, predicting an ala67-to-pro substitution in the second transmembrane domain of PMP22. The mutation was present in heterozygous state in all affected individuals. In light of the high levels of PMP22 transcript detected in the cochlea ({69:Robertson et al., 1994}), {32:Kovach et al. (1999)} suggested that this mutation may be responsible for deafness with the CMT phenotype. They speculated that the VIIIth nerve, which is surrounded by Schwann cells, was the most likely site of auditory neuropathy in this family. The prolongation of interpeak latencies in ABR (auditory brainstem responses) and/or the absence of ABR waveforms would generally be consistent with this putative site of the lesion. Unlike CMT associated with the PMP22 duplication and a gene dosage effect, the ala67-to-pro mutation was thought to cause a dominant-negative effect, like the majority of point mutations causing CMT and Dejerine-Sottas syndrome ({145900}). mutations PMP22, ALA67PRO number 10 clinvarAccessions RCV000008951;;2 status live name NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES text Whereas most HNPP ({162500}) cases are caused by a 1.5-Mb deletion in 17p, {93:Young et al. (1997)} identified a family with clinical and electrophysiologic features of HNPP, in which all affected members were heterozygous for a single base (G) insertion within a polyguanosine tract (nucleotides 325-330) in exon 3 (325insG). This mutation was predicted to result in a reading frameshift, starting at amino acid 95 and including 127 random amino acids. mutations PMP22, 1-BP INS, 325G number 11 clinvarAccessions RCV000008952;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT text In a family with Dejerine-Sottas syndrome ({145900}), {23:Ikegami et al. (1998)} identified a de novo mutation in the PMP22 gene. An abnormal fragment was seen on SSCP analysis of exon 4, and sequencing revealed a 2-bp deletion (CT) at nucleotides 426 and 427. Analysis of mRNA revealed a 2-base deletion with no splicing abnormalities. This would suggest that the reading frame would be altered at leucine-80 and would result in a protein that was longer by 49 amino acids. mutations PMP22, 2-BP DEL, 426CT number 12 clinvarAccessions RCV000008953;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT dbSnps rs104894624 text In a family with Dejerine-Sottas syndrome ({145900}), {23:Ikegami et al. (1998)} identified a mutation in the PMP22 gene using SSCP analysis. A G-to-T transversion was identified at nucleotide 636, which resulted in a glycine-to-cysteine substitution at codon 150 (gly150 to cys). The mutation created a new PvuII site. mutations PMP22, GLY150CYS number 13 clinvarAccessions RCV000008954;;1 status live name CHARCOT-MARIE-TOOTH DISEASE AND DEAFNESS dbSnps rs104894626 text In a family in which a father and 2 daughters had CMT1 with sensorineural deafness ({118300}), {6:Boerkoel et al. (2002)} identified an 82T-to-C transition in the PMP22 gene, resulting in a trp28-to-arg (W28R) substitution. mutations PMP22, TRP28ARG number 14 clinvarAccessions RCV000023072;;2 status live name CHARCOT-MARIE-TOOTH DISEASE AND DEAFNESS text In 3 affected members of a family with autosomal dominant CMT with deafness ({118300}), {71:Sambuughin et al. (2003)} identified a 12-bp deletion in exon 4 of the PMP22 gene, resulting in the deletion of 4 amino acids: ala, ile, tyr, and thr, at positions 115-118. The deletion occurs at the border of the third transmembrane domain and extracellular component of the protein. mutations PMP22, 12-BP DEL number 15 clinvarAccessions RCV000023073;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A, WITH FOCALLY FOLDED MYELIN SHEATHS dbSnps rs104894627 text {12:Fabrizi et al. (1999)} reported a family in which 4 individuals over 4 generations had severe CMT1A with focal myelin thickenings ({118220}) with a regular fusiform contour (tomacula) or a coarsely granular appearance. Ultrastructural examination disclosed uncompacted myelin and redundant irregular myelin loops. All affected patients had a heterozygous 159A-T mutation in the PMP22 gene, resulting in an asp37-to-val (D37V) substitution in the first extracellular loop of the protein. mutations PMP22, ASP37VAL number 16 clinvarAccessions RCV000008955;;1 status live name NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES dbSnps rs104894623 text In a girl with HNPP ({162500}), {56:Nodera et al. (2003)} identified a 199G-A transition in the PMP22 gene, resulting in an ala67-to-thr (A67T) substitution. The patient first developed symptoms at age 9 years and was examined again at age 17 years. She had ulnar neuropathy at the wrist and a diffuse distal sensorimotor demyelinative polyneuropathy. Her mother, who had a subclinical demyelinating polyneuropathy, also had the mutation. The authors noted that mutation in the same codon (A67P; {601097.0010}) had been reported in patients with CMT 1A and deafness ({118300}). mutations PMP22, ALA67THR number 17 clinvarAccessions RCV000008956;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL RECESSIVE dbSnps rs28936682 text In 3 sibs with Dejerine-Sottas syndrome ({145900}), {59:Parman et al. (1999)} identified a homozygous 518C-T change in the PMP22 gene, resulting in an arg157-to-trp (R157W) substitution. The unaffected parents were related as first cousins and both were heterozygous for the mutation. All 3 sibs showed a classic DSS phenotype, with delayed milestones, ataxia, distal muscle weakness and wasting, impaired sensation, pes cavus, and scoliosis. Nerve biopsy in 1 patient showed demyelination and onion bulb formation. The mutation occurred in the intracellular domain of PMP22. {59:Parman et al. (1999)} commented that DSS caused by mutation in the PMP22 gene is usually autosomal dominant, caused by a heterozygous mutation, and that the findings in this family demonstrate autosomal recessive inheritance. mutations PMP22, ARG157TRP number 18 clinvarAccessions RCV000008957;;1 status live name NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES dbSnps rs104894625 text In affected members of a family from Cyprus with HNPP ({162500}) and/or CMT1A ({118220}), {29:Kleopa et al. (2004)} identified a 65C-T transition in exon 1 of the PMP22 gene, resulting in a ser22-to-phe (S22F) substitution. One patient presented with typical HNPP, which later progressed to severe CMT1A, 2 patients had HNPP with features of CMT1A, and 1 patient had a chronic asymptomatic CMT1A phenotype. {29:Kleopa et al. (2004)} emphasized the broad phenotypic spectrum resulting from mutations in the PMP22 gene, as well as the phenotypic overlap of HNPP and CMT1A. mutations PMP22, SER22PHE number 19 alternativeNames CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A, INCLUDED clinvarAccessions RCV000008959;;2;;;RCV000008958;;1 status live name DEJERINE-SOTTAS SYNDROME, AUTOSOMAL RECESSIVE text {2:Al-Thihli et al. (2008)} reported a 7-year-old boy with autosomal recessive Dejerine-Sottas disease ({145900}) associated with compound heterozygous deletions in the PMP2 gene: the common 1.5-Mb deletion ({601097.0004}), inherited from the mother, and a deletion encompassing exons 2 and 3, inherited from the father. The nonconsanguineous parents were each heterozygous for a deletion and showed an HNPP ({162500}) phenotype. The boy had a severe phenotype with significantly delayed motor development, pes cavus, scoliosis, hyporeflexia, hearing deficits, severe demyelination on sural nerve biopsy, and gastroesophageal reflux. {2:Al-Thihli et al. (2008)} commented that the deletions in this patient were the largest compound heterozygous PMP22 deletions reported in the literature. mutations PMP22, EX2-3DEL number 20 alternativeNames NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES, INCLUDED clinvarAccessions RCV000008961;;1;;;RCV000008960;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A text In a 20-year-old man with severe CMT1A ({118220}), {54:Niedrist et al. (2009)} identified a heterozygous 1-bp deletion (281delG) in the last exon (exon 5) of the PMP22 gene, resulting in a C-terminally truncated protein. The transcript escapes nonsense-mediated mRNA decay. The mutant allele also carried the T118M ({601097.0005}) substitution in cis. Analysis of the parents showed that the 281delG mutation occurred de novo on the paternal allele, because the unaffected father was heterozygous for the T118M substitution. The findings suggested that the T118M substitution may not be pathogenic, although electrophysiologic studies were not performed on the father. The patient had delayed walking and initially walked on tiptoes. On examination at age 20 years, he had weakness in the legs while walking, pes cavus, kyphoscoliosis, hammertoes, and gait disturbance. There was atrophy of the lower leg muscles and intrinsic plantar feet muscles, as well as distal sensory vibratory loss in the lower limbs. Median nerve conduction velocities were not obtainable. mutations PMP22, 1-BP DEL, 281G number 21 clinvarAccessions RCV000023074;;1 status live name CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A text In 2 unrelated patients with a severe form of CMT1A ({118220}), {35:Liu et al. (2014)} identified a 1.4-Mb triplication of the PMP22 gene. Each individual was part of a family with autosomal dominant CMT1A in which the other affected family members had a 1.4-Mb duplication ({601097.0001}) and a more typical CMT1A phenotype that was less severe. In both families, molecular analysis of the triplication indicated that it occurred on the chromosome with the duplication and arose from the duplication during meiosis in the affected mother. Haplotype analysis indicated 2 different mechanisms: in 1 family, the triplication arose via intrachromosomal nonallelic homologous recombination (NAHR), whereas in the other family it arose from intrachromosomal NAHR followed by a gene-conversion event that most likely exchanged alleles between the maternal homologous chromosomes. A review of a database for CMT1A duplication testing identified 13% with duplication and 0.024% with a duplication-to-triplication event. These findings suggested that the rate of duplication to triplication is higher than that of de novo duplication. {35:Liu et al. (2014)} proposed that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication may be underestimated. The inheritance pattern in this scenario resembles genetic anticipation and has implications for genetic counseling. mutations PMP22, 1.4-MB TRIPLICATION number 22 clinvarAccessions RCV000114955;;1 prefix * titles alternativeTitles GROWTH ARREST-SPECIFIC 3; GAS3 preferredTitle PERIPHERAL MYELIN PROTEIN 22; PMP22 textSectionList textSection textSectionTitle Description textSectionContent The PMP22 gene encodes a 22-kD protein that comprises 2 to 5% of peripheral nervous system myelin. It is produced primarily by Schwann cells and expressed in the compact portion of essentially all myelinated fibers in the peripheral nervous system ({77:Snipes et al., 1992}). textSectionName description textSectionTitle Cloning textSectionContent {73:Schneider et al. (1988)} cloned a family of growth arrest-specific (Gas) genes in the mouse by subtractive hybridization based on differential expression in quiescent and growing NIH 3T3 fibroblasts. Using a cDNA of the mouse Gas3 gene to screen a human lung fibroblast cDNA library, {45:Martinotti et al. (1992)} isolated a partial human cDNA homolog. By screening a human fetal spinal cord cDNA library, {18:Hayasaka et al. (1992)} isolated a full-length cDNA of human PMP22 encoding a deduced 160-amino acid protein with high sequence similarity to the mouse, rat, and bovine proteins. {60:Patel et al. (1992)} cloned the human PMP22 gene and showed 87% and 86% amino acid identity with rat and mouse PMP22, respectively. An N-linked glycosylation sequence and membrane-associated regions of the protein were especially highly conserved. Three transcripts of 1.8, 1.3, and 0.8 kb were detected at high levels in the spinal cord and femoral nerve (peripheral nerve). {11:Edomi et al. (1993)} also cloned and determined the sequence of the human PMP22 gene. {43:Manfioletti et al. (1990)} determined that the Gas3 protein product is a transmembrane glycoprotein. {5:Ben-Porath and Benvenisty (1996)} reported that the amino acid identity among PMP22, epithelial membrane protein-1 (EMP1; {602333}), EMP2 ({602334}), and EMP3 ({602335}) ranges from 33 to 43%, with highest homology in the transmembrane regions. In addition, all 4 proteins contain 1 to 3 potential N-linked glycosylation sites in the first extracellular loop. The authors stated that these proteins comprise a novel family and also noted that the lens-specific membrane protein MP20 is distantly related. textSectionName cloning textSectionTitle Mapping textSectionContent {10:Colombo et al. (1992)} determined the chromosomal localization of 6 Gas genes in the mouse, and found that Gas3 was localized on mouse chromosome 11, about 44 cM proximal to the gene for p53. {45:Martinotti et al. (1992)} demonstrated that the human homolog of Gas3 (PMP22) maps to 17p13-p12 by analysis of human-rodent somatic cell hybrids and in situ hybridization to human metaphases. {60:Patel et al. (1992)} isolated cDNA and genomic clones for human PMP22 and showed by Southern analysis of somatic cell hybrids that the gene maps to 17p12-p11.2. {82:Takahashi et al. (1992)} mapped the PMP22 gene to 17p11.2 by FISH. textSectionName mapping textSectionTitle Gene Function textSectionContent PMP22 is a major component of myelin expressed in the compact portion of essentially all myelinated fibers in the peripheral nervous system and is produced predominantly by Schwann cells. Studies in injured nerve suggested a role during Schwann cell growth and differentiation ({78:Spreyer et al., 1991}, {77:Snipes et al., 1992}). {45:Martinotti et al. (1992)} suggested a possible role of the PMP22 gene in the development of neoplasia in patients with neurofibromatosis ({162200}), and in the myelin degenerative Charcot-Marie-Tooth disease linked to chromosome 17p (CMT1A; {118220}). PMP22 is expressed in cranial nerves but not in the mature central nervous system; however, during development it is expressed initially in all 3 germ layers and subsequently in migratory neural crest cells ({15:Hagedorn et al., 1999}; {92:Wulf et al., 1999}). These observations suggested that mutations in PMP22 might cause sensorineural deafness by demyelination of the eighth cranial nerve or by maldevelopment of the inner ear, which is a neural crest derivative, or by a combination of the 2. The rarity of severe deafness among families with PMP22 mutations suggests that most PMP22 mutations have minimal effects on inner ear development or cranial nerve myelination ({6:Boerkoel et al., 2002}). textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent PMP22 Duplication and Deletion {39:Lupski et al. (1991)} and {62:Raeymaekers et al. (1991)} found that a DNA duplication on chromosome 17p11 was the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; {118220}) (see {601097.0001} for a full discussion). {60:Patel et al. (1992)} showed that the PMP22 gene is located entirely within the CMT1A duplication region and that PMP22 is duplicated, but not disrupted, in CMT1A patients. They suggested that a gene dosage effect underlies, at least partially, the demyelinating neuropathy in CMT1A. {88:Valentijn et al. (1992)} likewise showed that the PMP22 gene is located within the CMT1A duplication and concluded that increased gene dosage may be responsible for the disorder in CMT1A. Using pulsed field gel electrophoresis and YACs, {83:Timmerman et al. (1992)} and {47:Matsunami et al. (1992)} also demonstrated that the PMP22 gene is contained within the CMT1A duplication. In patients with hereditary neuropathy with liability to pressure palsies (HNPP; {162500}), {8:Chance et al. (1993)} identified an interstitial deletion of distal 17p11.2 which included the PMP22 gene ({601097.0004}). {85:Umehara et al. (1995)} found deletions in 17p11.2 in 2 unrelated Japanese families with HNPP. {14:Gonnaud et al. (1995)} found interstitial deletions of the 17p11.2 region in affected and unaffected members of 4 unrelated families, including an affected woman who did not receive the paternal allele for PMP22. In studying the duplication, {61:Pentao et al. (1992)} identified several low copy number repetitive elements (REP) in 17p12-p11.2, including a large (more than 17 kb) CMT1A-REP unit. They determined that the PMP22 gene is located between 2 homologous CMT1A-REPs, and that the CMT1A duplication is a tandem repeat of 1.5 Mb of DNA. CMT1A-REP flanked the 1.5-Mb CMT1A monomer unit on normal chromosome 17 and was present in an additional copy on the CMT1A duplicated chromosome. {61:Pentao et al. (1992)} proposed that the de novo CMT1A duplication arose from unequal crossing over due to misalignment at the CMT1A-REP repeat sequences during meiosis. {58:Palau et al. (1993)} proved this was indeed the case. They studied the parental origin of the duplication in 9 genetically sporadic CMT1A patients and demonstrated that in all cases the mutation was the product of an unequal nonsister chromatid exchange during spermatogenesis. They suggested that male-specific factors may be operating during spermatogenesis to help in the formation of the duplication and/or stabilization of the duplicated chromosome. {36:Lopes et al. (1996)} developed a restriction map of the proximal and distal CMT1A-REPs. The combined use of cloned EcoRI fragments of the CMT1A-REPs and 3 different restriction enzymes permitted localization of the crossover breakpoints in 38 unrelated cases of HNPP and 76 unrelated cases of CMT1A that they analyzed. In 75% of patients the recombination breakpoint was localized within a 3.2-kb fragment of the CMT1A-REP. The remaining patients, with 1 exception, exhibited crossovers within a more telomeric 4.6-kb fragment. {36:Lopes et al. (1996)} noted that the strict coincidence of breakpoints in HNPP and CMT1A patients reinforces the hypothesis that duplication and deletion in the 17p11.2 region are mirror consequences of the same molecular event, namely, unequal recombination. They concluded that the 3.2-kb region where most recombination events occur probably contains sequences that promote recombination. {36:Lopes et al. (1996)} further reported that there are expressed sequences encoded in the CMT1A-REPs. They emphasized that close to 100% of the rearrangements present in HNPP and CMT1A can be detected with classic Southern blot methodology and appropriate probes, and that the extensive homology between distal and proximal CMT1A imposes constraints on PCR-based diagnosis. {24:Ikegami et al. (1997)} described a useful method for rapid diagnosis of the DNA duplication associated with CMT1A. They used a 1.0-kb EcoRI-PstI DNA fragment from the proximal CMT1A-REP repeat as a probe for Southern blot analysis and detected gene dosage in CMT1A by measuring radioactivity ratios with a photostimulated luminescence imaging plate. {65:Reiter et al. (1996)} identified the molecular etiology of the homologous recombination event that is responsible for the unequal crossing-over resulting in either duplication or deletion of the CMT1A gene in Charcot-Marie-Tooth disease and HNPP. Through the detection of novel junction fragments from the recombinant CMT1A-REPs in both CMT1A and HNPP patients, they identified a 1.7-kb recombination hotspot within the 30-kb CMT1A-REPs. This hotspot showed 98% identity between the 2 CMT1A-REPs, indicating that sequence identity is probably not the sole factor involved in promoting crossover events. Sequence analysis revealed a 'mariner' transposon-like element near the hotspot of homologous recombination, which the authors referred to as MITE, for 'mariner insect transposon-like element.' {65:Reiter et al. (1996)} hypothesized that the MITE could mediate strand exchange events via cleavage by a transposase at or near the 3-prime end of the element. {17:Hartl (1996)} reviewed the molecular biology of the MITE in relation to CMT1A. {64:Reiter et al. (1998)} followed up on their previous observations ({65:Reiter et al., 1996}) and found that in this hotspot, the relative risk of an exchange event was 50 times higher than in the surrounding 98.7% identical sequence shared by the 2 repeats. To refine the region of exchange further, they designed a PCR strategy to amplify the recombinant CMT1A-REP from HNPP patients as well as the proximal and distal CMT1A-REPs from control individuals. By comparing the sequences across recombinant REPs to that of the proximal and distal REPs, the exchange was mapped to a 557-basepair region within the previously identified 1.7-kb hotspot in 21 of 23 unrelated HNPP deletion patients. Two patients had recombined sequences suggesting an exchange event closer to the MITE previously identified near the hotspot. The studies provided direct observation of human meiotic recombination products. These results were considered consistent with the hypothesis that the minimum efficient processing segments, which have been characterized in E. coli, yeast, and cultured mammalian cells, may be required for efficient homologous meiotic recombination in humans. {37:Lopes et al. (1999)} reported a series of CMT1A patients in whom 50 of 59 chromosomal rearrangements were of paternal origin, and 54 of 59 were interchromosomal in nature. By sequencing the crossover hotspot in 28 patients with CMT1A or HNPP, the authors discovered chimeric sequences between proximal and distal repeat sequences in the region (CMT1A-REPs), suggesting conversion of DNA segments associated with the crossing-over. The finding of rearrangements supported a double-strand break (DSB) repair model, which was first described in yeast ({81:Szostak et al., 1983}). Successive steps of this model are heteroduplex DNA formation, mismatch correction, and gene conversion. The authors hypothesized that the DSB repair model of DNA exchange may apply universally from yeasts to humans. Studies of CMT1A patients showed that the majority of unequal crossovers occurred within a small region (less than 1 kb) of the 24-kb repeats (REPs), suggesting the presence of a recombination hotspot. {16:Han et al. (2000)} directly measured the frequency of unequal recombination in the hotspot region using sperm from 4 normal individuals. Surprisingly, unequal recombination between the REPs occurred at a rate no greater than the average rate for the male genome (approximately 1 cM/Mb) and was the same as that expected for equally aligned REPs. The authors remarked that a similar finding is seen in yeast, where recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. The CMT1A hotspot appears to stand in sharp contrast to the human MS32 minisatellite-associated hotspot, which exhibits highly enhanced recombination initiation in addition to positional specificity. The authors hypothesized that the CMT1A hotspot may consist of a region with genome-average recombination potential embedded within a recombination coldspot. {28:King et al. (1998)} described a patient with CMT1A caused by duplication of the PMP22 gene through an unusual mechanism: unbalanced translocation of 17p to the X chromosome. This finding further supported the hypothesis of gene dosage as the basis of CMT1A. {46:Matise et al. (1994)} referred to the tandem duplication underlying CMT1A as resulting in segmental trisomy. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within the duplication. {46:Matise et al. (1994)} demonstrated that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. They devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. {1:Aarskog and Vedeler (2000)} described a quantitative PCR method for detecting both duplication and deletion of the PMP22 gene in CMT1A and HNPP, respectively. Their method of real-time quantitative PCR is a sensitive, specific, and reproducible method allowing 13 patients to be diagnosed in 2 hours. It involves no radioisotopes and requires no post-PCR handling. {30:Korn-Lubetzki et al. (2002)} identified the deletion in the PMP22 gene ({601097.0004}) typical of HNPP in 3 members of family with inflammatory demyelinating polyneuropathy (see {139393}). {94:Zhang et al. (2009)} provided evidence that human genomic rearrangements ranging in size from several megabases to a few hundred basepairs can be generated by FoSTeS (fork stalling and template switching)/MMBIR (microhomology-mediated break-induced replication). Furthermore, they showed that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. {94:Zhang et al. (2009)} concluded that the FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis and exon shuffling, suggesting an important role in both genome and single-gene evolution. The authors examined the underlying mechanisms of potentially pathogenic copy number variations (CNVs) involving PMP22 and detected an apparently mitotically generated FoSTeS/MMBIR-mediated complex PMP22 rearrangement in the unaffected mother of 2 children with neuropathy. In a follow-up article, {95:Zhang et al. (2010)} studied a total of 21 individuals with rare CNVs of atypical sizes associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analysis. Seventeen unique CNVs, including 2 genomic deletions, 10 genomic duplications, 2 complex rearrangements, and 3 small exonic deletions were identified. Each of the CNVs included either the entire PMP22 gene, certain exons only, or ultraconserved potential regulatory sequences upstream of the PMP22 gene. Breakpoint sequence analysis revealed various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms such as FoSTeS and/or MMBIR that generated nonrecurrent rearrangements associated with neuropathy. {95:Zhang et al. (2010)} concluded that rare CNVs may potentially represent an important portion of missing heritability for human diseases, and confirmed that it is dosage alteration of the PMP22 gene that results in the neuropathy phenotypes associated with CNVs at chromosome 17p11. {9:Choi et al. (2011)} reported 3 Korean families with CMT1A due to 3 different nonrecurrent partial duplications of chromosome 17p12 involving the PMP22 gene. One family (FC116) was very large with multiple affected individuals spanning several generations, another (FC388) consisted of an affected mother and her 2 affected children, and the third (FC85) was a patient with sporadic disease. The phenotype was similar to other patients with CMT1A, although there was broad intrafamilial variability in family FC116. The duplications ranged in size from 465 to 725 kb. The duplications in the 2 smaller families were shown to occur de novo, as the unaffected parents did not carry the duplication. The breakpoint regions of 2 of the duplications could be assessed by PCR. In family FC116, the breakpoints occurred within 2 different Alu sequence families with a 34-bp exact microhomology. The haplotypes of the duplicated region were the same in all affected family members except 1. In family FC388, the breakpoints were within a long terminal repeat (LTR) sequence and an intron of the CDRT4 gene with a 3-bp 'TCA' microhomology and the duplication was associated with an 11-bp deletion. The putative mechanism in family FC116 was FoSTeS/MMBIR as described by {94:Zhang et al. (2009)}, whereas the duplicated region in family FC388 may have had a more complex etiology also involving recombination during meiosis. Point Mutations {50:Nelis et al. (1998)} analyzed the nerve-specific promoter and the noncoding exon 1A of the PMP22 gene in 15 unrelated patients with CMT1A and 16 unrelated patients with HNPP and found only 1 base change in exon 1A. In 1 autosomal dominant CMT1A patient, however, this base change did not cosegregate with the disease in the family (see {608236}). {66:Roa et al. (1993)} identified point mutations in the PMP22 gene in patients with Dejerine-Sottas syndrome (DSS; {145900}), a severe form of peripheral neuropathy with congenital, infantile, or juvenile onset ({601097.0006}). Although the change in PMP22 in Dejerine-Sottas syndrome is usually a point mutation or deletion, {76:Silander et al. (1996)} described duplication in PMP22 in patients who seemed to fit the clinical description of Dejerine-Sottas syndrome. {29:Kleopa et al. (2004)} reported a family from Cyprus in which 4 affected individuals had features of HNPP and/or CMT1A. One patient presented with typical HNPP, which later progressed to severe CMT1, 2 patients had HNPP with features of CMT1, and 1 patient had a chronic asymptomatic CMT1 phenotype. All 4 patients had the same heterozygous point mutation in the PMP22 gene ({601457.0019}). {29:Kleopa et al. (2004)} emphasized the broad phenotypic spectrum resulting from mutations in the PMP22 gene, as well as the phenotypic overlap of HNPP and CMT1A. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent {51:Nelis et al. (1999)} tabulated 27 distinct mutations in the PMP22 gene causing CMT1A. In general, the phenotype of the PMP22 missense mutations tended to be more severe than that of the CMT1A duplication. All but 1 (a frameshift) of these mutations were localized in the putative transmembrane domains of PMP22, indicating the functional importance of these domains. {6:Boerkoel et al. (2002)} pointed out that 2 mutations in the PMP22 gene that cause CMT1 with deafness ({118300}), W28R ({601097.0014}) and A67P ({601097.0010}), are located at the base of the first extracellular loop; thus, these mutations might be adjacent in the protein and effect hearing loss through a common mechanism. {71:Sambuughin et al. (2003)} identified a 12-bp deletion ({601097.0015}) in the PMP22 gene in a family with CMT1 and deafness, and noted that the mutation, like W28R and A67P, is located at the border of a transmembrane domain and an adjacent extracellular component. {19:Hodapp et al. (2006)} reported 3 unrelated families in which individuals had mutations in the PMP22 gene and another neurogenetic disease mutation. In 1 family, 2 brothers had duplication of the PMP22 gene, inherited from their father, and a missense mutation in the GJB1 gene ({304040}) inherited from their mother. The resulting CMT phenotype was severe in the 2 brothers, with one dying at age 11 years. In the second family, a woman had a PMP22 duplication and a repeat CTG expansion in the DMPK gene ({605377.0001}), with a severe phenotype comprising both CMT and myotonic dystrophy (DM1; {160900}). In the third family, a man had a PMP22 deletion and a mutation in the ABCD1 gene ({300371}), with a severe phenotype comprising HNPP and spasticity associated with adrenoleukodystrophy (ALD; {300100}). {19:Hodapp et al. (2006)} noted that the 2 simultaneous mutations were additive, leading to neurologic phenotypes in these families that were more severe than expected for each individual disease. textSectionName genotypePhenotypeCorrelations textSectionTitle Animal Model textSectionContent In a review of hereditary motor and sensory neuropathies, {90:Vance (1991)} pointed to the autosomal dominant 'Trembler' mutation (Tr) in the mouse as a possibly homologous condition. A hypomyelin neuropathy with onion bulb formation develops in older animals. In 2 allelic forms of the Trembler mouse, {79,80:Suter et al. (1992, 1992)} demonstrated point mutations in 2 distinct putative membrane-associated domains of the PMP22 gene. {74:Sereda et al. (1996)} generated a transgenic rat model of CMT1A and provided experimental evidence that CMT1A is caused by increased expression of PMP22. PMP22 transgenic rats developed gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resembled recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely failed to elaborate myelin. {70:Sahenk et al. (1999)} grafted sural nerve segments from patients with PMP22 duplications (CMT1A) or deletions (HNPP) into the cut ends of sciatic nerves of nude mice. Both grafts showed delayed onset of myelination compared to controls. PMP duplication xenografts showed proximal axonal enlargement with an increase in neurofilament and mitochondria density, suggesting an impairment of axonal transport. Distally, there was a decrease in myelin thickness with evidence of axonal loss, axonal degeneration and regeneration, and onion bulb formation. Changes from HNPP xenografts were similar, but more modest. {70:Sahenk et al. (1999)} concluded that PMP22 mutations in Schwann cells cause perturbations in the normal axonal cytoskeletal organization that underlie the pathogenesis of these hereditary disorders. Using the rat transgenic model for CMT1A, {55:Niemann et al. (2000)} showed that Schwann cells segregated with axons in the normal 1:1 ratio but remained arrested at the promyelinating stage, apparently unable to elaborate myelin sheaths. {55:Niemann et al. (2000)} examined gene expression of these dysmyelinating Schwann cells using semiquantitative RT-PCR and immunofluorescence analysis. Unexpectedly, Schwann cell differentiation appeared to proceed normally at the molecular level when monitored by the expression of mRNAs encoding major structural proteins of myelin. Furthermore, an aberrant coexpression of early and late Schwann cell markers was observed. PMP22 itself acquired complex glycosylation, suggesting that trafficking of the myelin protein through the endoplasmic reticulum is not significantly impaired. {55:Niemann et al. (2000)} suggested that PMP22, when overexpressed, accumulates in a late Golgi-cell membrane compartment and uncouples myelin assembly from the underlying program of Schwann cell differentiation. Using a genomewide, phenotype-driven, large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, {26:Isaacs et al. (2000)} identified 2 mutant mice with marked resting tremor. Backcross animals were generated using in vitro fertilization, and genome scans performed on DNA pools derived from multiple mutant mice. The mutation in each mouse was mapped to a region on chromosome 11 containing Pmp22. One Pmp22 mutation, his12 to arg, altered the same amino acid as in the severe human peripheral neuropathy Dejerine-Sottas syndrome (see {601097.0008}), while the other mutation, tyr153 to ter, truncated the Pmp22 protein by 7 amino acids. Histologic analysis of both lines revealed hypomyelination of peripheral nerves. {84:Tobler et al. (2002)} noted that common Pmp22 point mutations include L16P ({601097.0002}) in Trembler J (TrJ) mice and G150D in Tr mice. The same mutations have been found in humans. The Tr and TrJ phenotypes are not identical. In mice, the Tr mutation is dominant, and the TrJ mutation is semidominant over the wildtype allele. The homozygous TrJ genotype leads to a more severe peripheral myelin deficiency and a much shorter life span compared with the long-living homozygous Tr mice. Moreover, because the heterozygous Tr and TrJ mice display a more severe disease phenotype than the heterozygous Pmp22 knockout mice, both mutant alleles must act via gain-of-function or dominant-negative mechanisms. {84:Tobler et al. (2002)} found that all 3 Pmp22s (wildtype, Tr, and TrJ) formed complexes larger than dimers, with Tr Pmp22 especially prone to aggregate into high molecular weight complexes. Despite differences in aggregation of Tr and TrJ Pmp22, these 2 mutant Pmp22s sequestered the same amount of wildtype Pmp22 in heterodimers and heterooligomers. Thus, the differences in the phenotypes of Tr and TrJ mice may depend more on the ability of the mutant protein to aggregate than on the dominant-negative effect of the mutant Pmp22 on wildtype Pmp22 trafficking. {72:Saporta et al. (2011)} observed that complete absence of Pmp22 had a differential effect on myelination between motor and sensory nerve fibers in young mice. Whereas axonal loss affected both ventral motor and dorsal sensory roots equally at ages 10 to 13 months, younger mice had immature Schwann cells that did not form myelin at ventral roots, but there were fully differentiated Schwann cells at the dorsal roots. These data suggested that complete Pmp22 deficiency delays maturation of Schwann cells particularly in motor nerve fibers. textSectionName animalModel geneMapExists true editHistory carol : 04/25/2014 carol : 4/25/2014 mcolton : 4/23/2014 ckniffin : 4/23/2014 tpirozzi : 7/2/2013 ckniffin : 7/1/2013 carol : 3/25/2013 terry : 11/29/2012 alopez : 9/28/2012 ckniffin : 9/25/2012 carol : 9/14/2012 carol : 9/14/2012 terry : 5/16/2012 carol : 4/18/2012 ckniffin : 4/11/2012 wwang : 7/13/2010 ckniffin : 7/12/2010 wwang : 1/29/2010 ckniffin : 1/25/2010 alopez : 9/9/2009 terry : 9/4/2009 wwang : 4/15/2009 ckniffin : 3/3/2009 wwang : 4/10/2008 ckniffin : 4/1/2008 ckniffin : 8/15/2007 ckniffin : 2/15/2007 carol : 2/1/2007 wwang : 7/31/2006 ckniffin : 7/17/2006 wwang : 4/24/2006 ckniffin : 4/17/2006 wwang : 7/26/2005 ckniffin : 7/12/2005 tkritzer : 10/28/2004 ckniffin : 10/25/2004 terry : 5/5/2004 carol : 11/17/2003 ckniffin : 11/10/2003 cwells : 11/6/2003 carol : 10/2/2003 ckniffin : 10/1/2003 ckniffin : 10/1/2003 carol : 9/24/2003 ckniffin : 9/17/2003 cwells : 8/20/2003 ckniffin : 8/12/2003 ckniffin : 8/11/2003 carol : 5/12/2003 ckniffin : 5/2/2003 ckniffin : 5/1/2003 carol : 4/28/2003 ckniffin : 4/28/2003 ckniffin : 4/25/2003 ckniffin : 4/23/2003 ckniffin : 4/22/2003 terry : 4/16/2002 carol : 2/18/2002 mcapotos : 2/7/2002 terry : 1/31/2002 cwells : 5/11/2001 carol : 3/9/2001 cwells : 1/18/2001 terry : 1/10/2001 carol : 1/10/2001 terry : 12/19/2000 alopez : 9/22/2000 alopez : 9/22/2000 kayiaros : 7/13/1999 alopez : 6/14/1999 mgross : 6/14/1999 mgross : 4/5/1999 carol : 4/2/1999 mgross : 2/22/1999 mgross : 2/17/1999 terry : 2/10/1999 carol : 2/6/1999 terry : 2/4/1999 carol : 1/14/1999 terry : 1/12/1999 carol : 9/23/1998 alopez : 7/10/1998 carol : 7/1/1998 alopez : 6/9/1998 alopez : 6/3/1998 terry : 5/15/1998 terry : 5/12/1998 dholmes : 2/10/1998 mark : 7/16/1997 mark : 7/8/1997 jenny : 6/23/1997 terry : 2/7/1997 terry : 2/3/1997 terry : 1/27/1997 jamie : 1/21/1997 terry : 1/14/1997 carol : 6/24/1996 mark : 6/19/1996 mark : 6/19/1996 carol : 6/18/1996 mark : 6/17/1996 terry : 6/11/1996 mark : 5/8/1996 mark : 5/8/1996 terry : 4/15/1996 mark : 3/26/1996 mark : 3/13/1996 mark : 3/12/1996 mark : 3/6/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 3/5/1996 mark : 2/28/1996 mark : 2/28/1996 mark : 2/28/1996 dateCreated Wed, 28 Feb 1996 03:00:00 EST creationDate Victor A. McKusick : 2/28/1996 epochUpdated 1398409200 dateUpdated Fri, 25 Apr 2014 03:00:00 EDT referenceList reference articleUrl http://link.springer.de/link/service/journals/00439/bibs/0107005/01070494.htm publisherName Springer title Real-time quantitative polymerase chain reaction: a new method that detects both the peripheral myelin protein 22 duplication in Charcot-Marie-Tooth type 1A disease and the peripheral myelin protein 22 deletion in hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 1 publisherAbbreviation Springer pubmedID 11140948 source Hum. Genet. 107: 494-498, 2000. authors Aarskog, N. K., Vedeler, C. A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.32456 publisherName John Wiley & Sons, Inc. title Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype. mimNumber 601097 referenceNumber 2 publisherAbbreviation Wiley pubmedID 18698610 source Am. J. Med. Genet. 146A: 2412-2416, 2008. authors Al-Thihli, K., Rudkin, T., Carson, N., Poulin, C., Melancon, S., Der Kaloustian, V. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022510X97002189 publisherName Elsevier Science title Roussy-Levy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA associated with a duplication on chromosome 17p11.2. mimNumber 601097 referenceNumber 3 publisherAbbreviation ES pubmedID 9543325 source J. Neurol. Sci. 154: 72-75, 1998. authors Auer-Grumbach, M., Strasser-Fuchs, S., Wagner, K., Korner, E., Fazekas, F. pubmedImages false publisherUrl http://www.elsevier.com/ source Am. J. Hum. Genet. 59 (suppl.): A248 only, 1996. mimNumber 601097 authors Bathke, K. D., Ekici, A., Liehr, T., Grehl, H., Lupski, J. R., Neundorfer, B., Rautenstrauss, B. title The hemizygous thr118met amino acid exchange in peripheral myelin protein 22: recessive Charcot-Marie-Tooth (CMT) disease type 1 mutation or polymorphism? (Abstract) referenceNumber 4 title Characterization of a tumor-associated gene, a member of a novel family of genes encoding membrane glycoproteins. mimNumber 601097 referenceNumber 5 pubmedID 8996089 source Gene 183: 69-75, 1996. authors Ben-Porath, I., Benvenisty, N. pubmedImages false articleUrl http://dx.doi.org/10.1002/ana.10089 publisherName John Wiley & Sons, Inc. title Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. mimNumber 601097 referenceNumber 6 publisherAbbreviation Wiley pubmedID 11835375 source Ann. Neurol. 51: 190-201, 2002. authors Boerkoel, C. F., Takashima, H., Garcia, C. A., Olney, R. K., Johnson, J., Berry, K., Russo, P., Kennedy, S., Teebi, A. S., Scavina, M., Williams, L. L., Mancias, P., Butler, I. J., Krajewski, K., Shy, M., Lupski, J. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=17796454 publisherName HighWire Press title The Bar 'gene' a duplication. mimNumber 601097 referenceNumber 7 publisherAbbreviation HighWire pubmedID 17796454 source Science 83: 210-211, 1936. authors Bridges, C. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(93)90058-X publisherName Elsevier Science title DNA deletion associated with hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 8 publisherAbbreviation ES pubmedID 8422677 source Cell 72: 143-151, 1993. authors Chance, P. F., Alderson, M. K., Leppig, K. A., Lensch, M. W., Matsunami, N., Smith, B., Swanson, P. D., Odelberg, S. J., Disteche, C. M., Bird, T. D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s10048-010-0272-3 publisherName Springer title Inheritance of Charcot-Marie-Tooth disease 1A with rare nonrecurrent genomic rearrangement. mimNumber 601097 referenceNumber 9 publisherAbbreviation Springer pubmedID 21193943 source Neurogenetics 12: 51-58, 2011. authors Choi, B.-O., Kim, N. K., Park, S. W., Hyun, Y. S., Jeon, H. J., Hwang, J. H., Chung, K. W. pubmedImages false publisherUrl http://www.springeronline.com/ title Localization of growth arrest-specific genes on mouse chromosomes 1, 7, 8, 11, 13, and 16. mimNumber 601097 referenceNumber 10 pubmedID 1347472 source Mammalian Genome 2: 130-134, 1992. authors Colombo, M. P., Martinotti, A., Howard, T. A., Schneider, C., D'Eustachio, P., Seldin, M. F. pubmedImages false title Sequence of human GAS3/PMP22 full-length cDNA. mimNumber 601097 referenceNumber 11 pubmedID 8482547 source Gene 126: 289-290, 1993. authors Edomi, P., Martinotti, A., Colombo, M. P., Schneider, C. pubmedImages false articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10489052 publisherName HighWire Press title Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22. mimNumber 601097 referenceNumber 12 publisherAbbreviation HighWire pubmedID 10489052 source Neurology 53: 846-851, 1999. authors Fabrizi, G. M., Cavallaro, T., Taioli, F., Orrico, D., Morbin, M., Simonati, A., Rizzuto, N. pubmedImages false publisherUrl http://highwire.stanford.edu title Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). mimNumber 601097 referenceNumber 13 pubmedID 1564512 source J. Neurol. Sci. 107: 145-154, 1992. authors Gabreels-Festen, A. A. W. M., Joosten, E. M. G., Gabreels, F. J. M., Jennekens, F. G. I., Janssen-van Kempen, T. W. pubmedImages false title DNA analysis as a tool to confirm the diagnosis of asymptomatic hereditary neuropathy with liability to pressure palsies (HNPP) with further evidence for the occurrence of de novo mutations. mimNumber 601097 referenceNumber 14 pubmedID 8848937 source Acta. Neurol. Scand. 92: 313-318, 1995. authors Gonnaud, P. M., Sturtz, F., Fourbil, Y., Bonnebouche, C., Tranchant, C., Warter, J. M., Chazot, G., Bady, B., Vial, C., Brechard, A. S., Vandenberghe, A. pubmedImages false articleUrl http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10433908 publisherName HighWire Press title P0 and PMP22 mark a multipotent neural crest-derived cell type that displays community effects in response to TGF-beta family factors. mimNumber 601097 referenceNumber 15 publisherAbbreviation HighWire pubmedID 10433908 source Development 126: 3781-3794, 1999. authors Hagedorn, L., Suter, U., Sommer, L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10915777 publisherName HighWire Press title Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate. mimNumber 601097 referenceNumber 16 publisherAbbreviation HighWire pubmedID 10915777 source Hum. Molec. Genet. 9: 1881-1889, 2000. authors Han, L.-L., Keller, M. P., Navidi, W., Chance, P. F., Arnheim, N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0396-227 publisherName Nature Publishing Group title The most unkindest cut of all. mimNumber 601097 referenceNumber 17 publisherAbbreviation NPG pubmedID 8589708 source Nature Genet. 12: 227-229, 1996. authors Hartl, D. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(92)90820-B publisherName Elsevier Science title Isolation and sequence determination of cDNA encoding PMP-22 (PAS-II/SR13/Gas-3) of human peripheral myelin. mimNumber 601097 referenceNumber 18 publisherAbbreviation ES pubmedID 1497668 source Biochem. Biophys. Res. Commun. 186: 827-831, 1992. authors Hayasaka, K., Himoro, M., Nanao, K., Sato, W., Miura, M., Uyemura, K., Takahashi, E., Takada, G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=16401743 publisherName HighWire Press title Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. mimNumber 601097 referenceNumber 19 publisherAbbreviation HighWire pubmedID 16401743 source Arch. Neurol. 63: 112-117, 2006. Note: Erratum: Arch. Neurol. 63: 201 only, 2006. authors Hodapp, J. A., Carter, G. T., Lipe, H. P., Michelson, S. J., Kraft, G. H., Bird, T. D. pubmedImages false publisherUrl http://highwire.stanford.edu title De-novo mutation in hereditary motor and sensory neuropathy type I. mimNumber 601097 referenceNumber 20 pubmedID 1349106 source Lancet 339: 1081-1082, 1992. authors Hoogendijk, J. E., Hensels, G. W., Gabreels-Festen, A. A. W. M., Gabreels, F. J. M., Janssen, E. A. M., De Jonghe, P., Martin, J.-J., Van Broeckhoven, C., Valentijn, L. J., Baas, F., de Visser, M., Bolhuis, P. A. pubmedImages false title The duplication in Charcot-Marie-Tooth disease type 1a spans at least 1100 kb on chromosome 17p11.2. mimNumber 601097 referenceNumber 21 pubmedID 1721895 source Hum. Genet. 88: 215-218, 1991. authors Hoogendijk, J. E., Hensels, G. W., Zorn, I., Valentijn, L., Janssen, E. A. M., de Visser, M., Barker, D. F., Ongerboer de Visser, B. W., Baas, F., Bolhuis, P. A. pubmedImages false title Allelic heterogeneity in hereditary motor and sensory neuropathy type 1a (Charcot-Marie-Tooth disease type 1a). mimNumber 601097 referenceNumber 22 pubmedID 8492918 source Neurology 43: 1010-1015, 1993. authors Hoogendijk, J. E., Janssen, E. A. M., Gabreels-Festen, A. A. W. M., Hensels, G. W., Joosten, E. M. G., Gabreels, F. J. M., Zorn, I., Valentijn, L. J., Baas, F., Ongerboer de Visser, B. W., de Visser, M., Bolhuis, P. A. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/8102003/81020294.htm publisherName Springer title Novel mutations of the peripheral myelin protein 22 gene in two pedigrees with Dejerine-Sottas disease. mimNumber 601097 referenceNumber 23 publisherAbbreviation Springer pubmedID 9544841 source Hum. Genet. 102: 294-298, 1998. authors Ikegami, T., Ikeda, H., Aoyama, M., Matsuki, T., Imota, T., Fukuuchi, Y., Amano, T., Toyoshima, I., Ishihara, Y., Endoh, H., Hayasaka, K. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:6<563::AID-HUMU10>3.0.CO;2-0 publisherName John Wiley & Sons, Inc. title Facilitated diagnosis of CMT1A duplication in chromosome 17p11.2-12: analysis with a CMT1A-REP repeat probe and photostimulated luminescence imaging. mimNumber 601097 referenceNumber 24 publisherAbbreviation Wiley pubmedID 9195231 source Hum. Mutat. 9: 563-566, 1997. authors Ikegami, T., Ikeda, H., Chance, P. F., Kiyosawa, H., Yamamoto, M., Sobue, G., Ohnishi, A., Tachi, N., Hayasaka, K. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=9004143 publisherName HighWire Press title Dejerine-Sottas disease with sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness: de novo dominant point mutation of the PMP22 gene. mimNumber 601097 referenceNumber 25 publisherAbbreviation HighWire pubmedID 9004143 source J. Med. Genet. 33: 1048-1049, 1996. authors Ionasescu, V. V., Searby, C., Greenberg, S. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10915775 publisherName HighWire Press title Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy. mimNumber 601097 referenceNumber 26 publisherAbbreviation HighWire pubmedID 10915775 source Hum. Molec. Genet. 9: 1865-1871, 2000. authors Isaacs, A. M., Davies, K. E., Hunter, A. J., Nolan, P. M., Vizor, L., Peters, J., Gale, D. G., Kelsell, D. P., Latham, I. D., Chase, J. M., Fisher, E. M. C., Bouzyk, M. M., {and 11 others} pubmedImages false publisherUrl http://highwire.stanford.edu title Homozygous expression of a dominant gene for Charcot-Marie-Tooth neuropathy. mimNumber 601097 referenceNumber 27 pubmedID 475348 source Ann. Neurol. 5: 515-522, 1979. authors Killian, J. M., Kloepfer, H. W. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1998&volume=54&issue=5&spage=413 publisherName Blackwell Publishing title Charcot-Marie-Tooth phenotype produced by a duplicated PMP22 gene as part of a 17p trisomy-translocation to the X chromosome. mimNumber 601097 referenceNumber 28 publisherAbbreviation Blackwell pubmedID 9842994 source Clin. Genet. 54: 413-416, 1998. authors King, P. H., Waldrop, R., Lupski, J. R., Shaffer, L. G. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1007/s10048-004-0184-1 publisherName Springer title A novel PMP22 mutation ser22phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes. mimNumber 601097 referenceNumber 29 publisherAbbreviation Springer pubmedID 15205993 source Neurogenetics 5: 171-175, 2004. authors Kleopa, K. A., Georgiou, D.-M., Nicolaou, P., Koutsou, P., Papathanasiou, E., Kyriakides, T., Christodoulou, K. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/ajmg.10725 publisherName John Wiley & Sons, Inc. title Family with inflammatory demyelinating polyneuropathy and the HNPP 17p12 deletion. mimNumber 601097 referenceNumber 30 publisherAbbreviation Wiley pubmedID 12439896 source Am. J. Med. Genet. 113: 275-278, 2002. authors Korn-Lubetzki, I., Argov, Z., Raas-Rothschild, A., Wirguin, I., Steiner, I. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Charcot-Marie-Tooth disease with sensorineural hearing loss--an autosomal dominant trait. mimNumber 601097 referenceNumber 31 pubmedID 7139106 source Birth Defects Orig. Art. Ser. 18: 223-228, 1982. authors Kousseff, B. G., Hadro, T. A., Treiber, D. L., Wollner, T., Morris, C. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63660-X publisherName Elsevier Science title A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. mimNumber 601097 referenceNumber 32 publisherAbbreviation ES pubmedID 10330345 source Am. J. Hum. Genet. 64: 1580-1593, 1999. authors Kovach, M. J., Lin, J.-P., Boyadjiev, S., Campbell, K., Mazzeo, L., Herman, K., Rimer, L. A., Frank, W., Llewellyn, B., Jabs, E. W., Gelber, D., Kimonis, V. E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8541860 publisherName HighWire Press title Constant rearrangement of the CMT1A-REP sequences in HNPP patients with a deletion in chromosome 17p11.2: a study of 30 unrelated cases. mimNumber 601097 referenceNumber 33 publisherAbbreviation HighWire pubmedID 8541860 source Hum. Molec. Genet. 4: 1673-1674, 1995. authors LeGuern, E., Gouider, R., Lopes, J., Abbas, N., Gugenheim, M., Tardieu, S., Ravise, N., Leger, J.-M., Vallat, J.-M., Bouche, P., Agid, Y., Brice, A., {French CMT Collaborative Research Group} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=17620487 publisherName HighWire Press title Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 34 publisherAbbreviation HighWire pubmedID 17620487 source Arch. Neurol. 64: 974-978, 2007. Note: Erratum: Arch. Neurol. 64: 1547 only, 2007. authors Li, J., Ghandour, K., Radovanovic, D., Shy, R. R., Krajewski, K. M., Shy, M. E., Nicholson, G. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(14)00055-X publisherName Elsevier Science title Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication. mimNumber 601097 referenceNumber 35 publisherAbbreviation ES pubmedID 24530202 source Am. J. Hum. Genet. 94: 462-469, 2014. authors Liu, P., Gelowani, V., Zhang, F., Drory, V. E., Ben-Shachar, S., Roney, E., Medeiros, A. C., Moore, R. J., DiVincenzo, C., Burnette, W. B., Higgins, J. J., Li, J., Orr-Urtreger, A., Lupski, J. R. pubmedImages false publisherUrl http://www.elsevier.com/ title Recombination hot spot in a 3.2-kb region of the Charcot-Marie-Tooth type 1A repeat sequences: new tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie-Tooth type 1A. mimNumber 601097 referenceNumber 36 pubmedID 8651299 source Am. J. Hum. Genet. 58: 1223-1230, 1996. authors Lopes, J., LeGuern, E., Gouider, R., Tardieu, S., Abbas, N., Birouk, N., Gugenheim, M., Bouche, P., Agid, Y., Brice, A., {French CMT Collaborative Research Group} pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10545609 publisherName HighWire Press title Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP. mimNumber 601097 referenceNumber 37 publisherAbbreviation HighWire pubmedID 10545609 source Hum. Mol. Genet. 8: 2285-2292, 1999. authors Lopes, J., Tardieu, S., Silander, K., Blair, I., Vandenberghe, A., Palau, F., Ruberg, M., Brice, A., LeGuern, E. pubmedImages false publisherUrl http://highwire.stanford.edu title A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 38 pubmedID 7825607 source Am. J. Hum. Genet. 56: 91-98, 1995. authors Lorenzetti, D., Pareyson, D., Sghirlanzoni, A., Roa, B. B., Abbas, N. E., Pandolfo, M., Di Donato, S., Lupski, J. R. pubmedImages false source Chicago: Mosby-Yearbook (pub.) 1991. Pp. 1-25. mimNumber 601097 authors Lupski, J. R., Garcia, C. A., Parry, G. J., Patel, P. I. title Charcot-Marie-Tooth polyneuropathy syndrome: clinical, electrophysiological, and genetic aspects.In: Appel, S. : Current Neurology. referenceNumber 39 articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(91)90613-4 publisherName Elsevier Science title DNA duplication associated with Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 40 publisherAbbreviation ES pubmedID 1677316 source Cell 66: 219-232, 1991. authors Lupski, J. R., Montes de Oca-Luna, R., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B. J., Saucedo-Cardenas, O., Barker, D. F., Killian, J. M., Garcia, C. A., Chakravarti, A., Patel, P. I. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng0492-29 publisherName Nature Publishing Group title Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 41 publisherAbbreviation NPG pubmedID 1301995 source Nature Genet. 1: 29-33, 1992. authors Lupski, J. R., Wise, C. A., Kuwano, A., Pentao, L., Parke, J. T., Glaze, D. G., Ledbetter, D. H., Greenberg, F., Patel, P. I. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1552536 publisherName HighWire Press title Charcot-Marie-Tooth disease type 1a (CMT1a): evidence for trisomy of the region p11.2 of chromosome 17 in south Wales families. mimNumber 601097 referenceNumber 42 publisherAbbreviation HighWire pubmedID 1552536 source J. Med. Genet. 29: 12-13, 1992. authors MacMillan, J. C., Upadhyaya, M., Harper, P. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=1692961 publisherName HighWire Press title A growth arrest-specific (gas) gene codes for a membrane protein. mimNumber 601097 referenceNumber 43 publisherAbbreviation HighWire pubmedID 1692961 source Molec. Cell. Biol. 10: 2924-2930, 1990. authors Manfioletti, G., Ruaro, M. E., Del Sal, G., Philipson, L., Schneider, C. pubmedImages false publisherUrl http://highwire.stanford.edu title Dejerine-Sottas neuropathy and PMP22 point mutations: a new base pair substitution and a possible 'hot spot' on ser72. mimNumber 601097 referenceNumber 44 pubmedID 9585367 source Ann. Neurol. 43: 680-683, 1998. authors Marques, W., Jr., Thomas, P. K., Sweeney, M. G., Carr, L., Wood, N. W. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=1303210 publisherName HighWire Press title Isolation and mapping to 17p12-13 of the human homologous of the murine growth arrest specific Gas-3 gene. mimNumber 601097 referenceNumber 45 publisherAbbreviation HighWire pubmedID 1303210 source Hum. Molec. Genet. 1: 331-334, 1992. authors Martinotti, A., Cariani, C. T., Melani, C., Sozzi, G., Spurr, N. K., Pierotti, M. A., Colombo, M. P. pubmedImages false publisherUrl http://highwire.stanford.edu title Detection of tandem duplications and implications for linkage analysis. mimNumber 601097 referenceNumber 46 pubmedID 8198134 source Am. J. Hum. Genet. 54: 1110-1121, 1994. authors Matise, T. C., Chakravarti, A., Patel, P. I., Lupski, J. R., Nelis, E., Timmerman, V., Van Broeckhoven, C., Weeks, D. E. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0692-176 publisherName Nature Publishing Group title Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. mimNumber 601097 referenceNumber 47 publisherAbbreviation NPG pubmedID 1303231 source Nature Genet. 1: 176-179, 1992. authors Matsunami, N., Smith, B., Ballard, L., Lensch, M. W., Robertson, M., Albertsen, H., Hanemann, C. O., Muller, H. W., Bird, T. D., White, R., Chance, P. F. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ana.20434 publisherName John Wiley & Sons, Inc. title Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. mimNumber 601097 referenceNumber 48 publisherAbbreviation Wiley pubmedID 15786462 source Ann. Neurol. 57: 589-591, 2005. authors Meggouh, F., de Visser, M., Arts, W. F. M., De Coo, R. I. F. M., van Schaik, I. N., Baas, F. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ejhg.2009.29 publisherName Nature Publishing Group title Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. mimNumber 601097 referenceNumber 49 publisherAbbreviation NPG pubmedID 19259128 source Europ. J. Hum. Genet. 17: 1154-1159, 2009. authors Miltenberger-Miltenyi, G., Schwarzbraun, T., Loscher, W. N., Wanschitz, J., Windpassinger, C., Duba, H.-C., Seidl, R., Albrecht, G., Weirich-Schwaiger, H., Zoller, H., Utermann, G., Auer-Grumbach, M., Janecke, A. R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=9678704 publisherName HighWire Press title Mutation analysis of the nerve specific promoter of the peripheral myelin protein 22 gene in CMT1 disease and HNPP. mimNumber 601097 referenceNumber 50 publisherAbbreviation HighWire pubmedID 9678704 source J. Med. Genet. 35: 590-593, 1998. authors Nelis, E., De Jonghe, P., De Vriendt, E., Patel, P. I., Martin, J.-J., Van Broeckhoven, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:1<11::AID-HUMU2>3.0.CO;2-A publisherName John Wiley & Sons, Inc. title Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. mimNumber 601097 referenceNumber 51 publisherAbbreviation Wiley pubmedID 9888385 source Hum. Mutat. 13: 11-28, 1999. authors Nelis, E., Haites, N., Van Broeckhoven, C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng0197-13 publisherName Nature Publishing Group title PMP22 thr(118)met: recessive CMT1 mutation or polymorphism? (Letter) mimNumber 601097 referenceNumber 52 publisherAbbreviation NPG pubmedID 8988161 source Nature Genet. 15: 13-14, 1997. authors Nelis, E., Holmberg, B., Adolfsson, R., Holmgren, G., Van Broeckhoven, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0394-263 publisherName Nature Publishing Group title A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 53 publisherAbbreviation NPG pubmedID 8012388 source Nature Genet. 6: 263-266, 1994. Note: Erratum: Nature Genet. 7: 113 only 1994. authors Nicholson, G. A., Valentijn, L. J., Cherryson, A. K., Kennerson, M. L., Bragg, T. L., DeKroon, R. M., Ross, D. A., Pollard, J. D., Mcleod, J. G., Bolhuis, P. 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E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8111370 publisherName HighWire Press title Origin of the de novo duplication in Charcot-Marie-Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis. mimNumber 601097 referenceNumber 58 publisherAbbreviation HighWire pubmedID 8111370 source Hum. Molec. Genet. 2: 2031-2035, 1993. authors Palau, F., Lofgren, A., De Jonghe, P., Bort, S., Nelis, E., Sevilla, T., Martin, J.-J., Vilchez, J., Prieto, F., Van Broeckhoven, C. pubmedImages false publisherUrl http://highwire.stanford.edu title Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. mimNumber 601097 referenceNumber 59 pubmedID 10211478 source Ann. Neurol. 45: 518-522, 1999. authors Parman, Y., Plante-Bordeneuve, V., Guiochon-Mantel, A., Eraksoy, M., Said, G. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0692-159 publisherName Nature Publishing Group title The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 60 publisherAbbreviation NPG pubmedID 1303228 source Nature Genet. 1: 159-165, 1992. authors Patel, P. I., Roa, B. B., Welcher, A. A., Schoener-Scott, R., Trask, B. J., Pentao, L., Snipes, G. J., Garcia, C. A., Francke, U., Shooter, E. M., Lupski, J. R., Suter, U. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1292-292 publisherName Nature Publishing Group title Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. mimNumber 601097 referenceNumber 61 publisherAbbreviation NPG pubmedID 1303282 source Nature Genet. 2: 292-300, 1992. authors Pentao, L., Wise, C. A., Chinault, A. C., Patel, P. I., Lupski, J. R. pubmedImages false publisherUrl http://www.nature.com title Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). mimNumber 601097 referenceNumber 62 pubmedID 1822787 source Neuromusc. Disord. 1: 93-97, 1991. authors Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J. E., Baas, F., Barker, D. F., Martin, J. J., De Visser, M., Bolhuis, P. A., Van Broeckhoven, C., {HMSN Collaborative Research Group} pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1552545 publisherName HighWire Press title Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). mimNumber 601097 referenceNumber 63 publisherAbbreviation HighWire pubmedID 1552545 source J. Med. Genet. 29: 5-11, 1992. authors Raeymaekers, P., Timmerman, V., Nelis, E., Van Hul, W., De Jonghe, P., Martin, J.-J., Van Broeckhoven, C., {HMSN Collaborative Research Group} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61522-5 publisherName Elsevier Science title Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. mimNumber 601097 referenceNumber 64 publisherAbbreviation ES pubmedID 9545397 source Am. J. Hum. 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R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1193-269 publisherName Nature Publishing Group title Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. mimNumber 601097 referenceNumber 66 publisherAbbreviation NPG pubmedID 8275092 source Nature Genet. 5: 269-273, 1993. authors Roa, B. B., Dyck, P. J., Marks, H. G., Chance, P. F., Lupski, J. R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1093-189 publisherName Nature Publishing Group title Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 67 publisherAbbreviation NPG pubmedID 8252046 source Nature Genet. 5: 189-194, 1993. authors Roa, B. B., Garcia, C. A., Pentao, L., Killian, J. M., Trask, B. J., Suter, U., Snipes, G. J., Ortiz-Lopez, R., Shooter, E. M., Patel, P. I., Lupski, J. 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R. pubmedImages false articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12578939 publisherName HighWire Press title Deafness and CMT disease associated with a novel four amino acid deletion in the PMP22 gene. mimNumber 601097 referenceNumber 71 publisherAbbreviation HighWire pubmedID 12578939 source Neurology 60: 506-508, 2003. authors Sambuughin, N., de Bantel, A., McWilliams, S., Sivakumar, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://archneur.jamanetwork.com/article.aspx?doi=10.1001/archneurol.2011.110 publisherName Silverchair Information Systems title Neuropathy in a human without the PMP22 gene. mimNumber 601097 referenceNumber 72 publisherAbbreviation silverchair pubmedID 21670407 source Arch. Neurol. 68: 814-821, 2011. authors Saporta, M. A., Katona, I., Zhang, X., Roper, H. P., McClelland, L., Macdonald, F., Brueton, L., Blake, J., Suter, U., Reilly, M. M., Shy, M. 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P., Schneider, A., Hund, E., Meinck, H.-M., Suter, U., Nave, K.-A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ana.20777 publisherName John Wiley & Sons, Inc. title T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. mimNumber 601097 referenceNumber 75 publisherAbbreviation Wiley pubmedID 16437560 source Ann. Neurol. 59: 358-364, 2006. authors Shy, M. E., Scavina, M. T., Clark, A., Krajewski, K. M., Li, J., Kamholz, J., Kolodny, E., Szigeti, K., Fischer, R. A., Saifi, G. M., Scherer, S. S., Lupski, J. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1996)8:4<304::AID-HUMU2>3.0.CO;2-7 publisherName John Wiley & Sons, Inc. title A de novo duplication in 17p11.2 and a novel mutation in the P(0) gene in two Dejerine-Sottas syndrome patients. mimNumber 601097 referenceNumber 76 publisherAbbreviation Wiley pubmedID 8956034 source Hum. Mutat. 8: 304-310, 1996. authors Silander, K., Meretoja, P., Nelis, E., Timmerman, V., Van Broeckhoven, C., Aula, P., Savontaus, M.-L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jcb.org/cgi/pmidlookup?view=long&pmid=1556154 publisherName HighWire Press title Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). mimNumber 601097 referenceNumber 77 publisherAbbreviation HighWire pubmedID 1556154 source J. Cell Biol. 117: 225-238, 1992. authors Snipes, G. J., Suter, U., Welcher, A. A., Shooter, E. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Axon-regulated expression of a Schwann cell transcript that is homologous to a 'growth arrest-specific' gene. mimNumber 601097 referenceNumber 78 pubmedID 1935894 source EMBO J. 10: 3661-3668, 1991. authors Spreyer, P., Kuhn, G., Hanemann, C. O., Gillen, C., Schaal, H., Kuhn, R., Lemke, G., Muller, H. W. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1374899 publisherName HighWire Press title A leucine-to-proline mutation in the putative first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse. mimNumber 601097 referenceNumber 79 publisherAbbreviation HighWire pubmedID 1374899 source Proc. Nat. Acad. Sci. 89: 4382-4386, 1992. authors Suter, U., Moskow, J. J., Welcher, A. A., Snipes, G. J., Kosaras, B., Sidman, R. L., Buchberg, A. M., Shooter, E. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/356241a0 publisherName Nature Publishing Group title Trembler mouse carries a point mutation in a myelin gene. mimNumber 601097 referenceNumber 80 publisherAbbreviation NPG pubmedID 1552943 source Nature 356: 241-244, 1992. authors Suter, U., Welcher, A. A., Ozcelik, T., Snipes, G. J., Kosaras, B., Francke, U., Billings-Gagliardi, S., Sidman, R. L., Shooter, E. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(83)90331-8 publisherName Elsevier Science title The double-strand-break repair model for recombination. mimNumber 601097 referenceNumber 81 publisherAbbreviation ES pubmedID 6380756 source Cell 33: 25-35, 1983. authors Szostak, J. W., Orr-Weaver, T. L., Rothstein, R. J., Stahl, F. W. pubmedImages false publisherUrl http://www.elsevier.com/ title Localization of PMP-22 gene (candidate gene for the Charcot-Marie-Tooth disease 1A) to band 17p11.2 by direct R-banding fluorescence in situ hybridization. mimNumber 601097 referenceNumber 82 pubmedID 1297450 source Jpn. J. Hum. Genet. 37: 303-306, 1992. authors Takahashi, E., Takeda, O., Himoro, M., Nanao, K., Takada, G., Hayasaka, K. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0692-171 publisherName Nature Publishing Group title The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. mimNumber 601097 referenceNumber 83 publisherAbbreviation NPG pubmedID 1303230 source Nature Genet. 1: 171-175, 1992. Note: Erratum: Nature Genet. 2: 84 only, 1992. authors Timmerman, V., Nelis, E., Van Hul, W., Nieuwenhuijsen, B. W., Chen, K. L., Wang, S., Othman, K. B., Cullen, B., Leach, R. J., Hanemann, C. O., De Jonghe, P., Raeymaekers, P., van Ommen, G.-J. B., Martin, J.-J., Muller, H. W., Vance, J. M., Fischbeck, K. H., Van Broeckhoven, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11752407 publisherName HighWire Press title Differential aggregation of the Trembler and Trembler J mutants of peripheral myelin protein 22. mimNumber 601097 referenceNumber 84 publisherAbbreviation HighWire pubmedID 11752407 source Proc. Nat. Acad. Sci. 99: 483-488, 2002. authors Tobler, A. R., Liu, N., Mueller, L., Shooter, E. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Deletion in chromosome 17p11.2 including the peripheral myelin protein-22 (PMP-22) gene in hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 85 pubmedID 8583222 source J. Neurol. Sci. 133: 173-176, 1995. authors Umehara, F., Kiwaki, T., Yoshikawa, H., Nishimura, T., Nakagawa, M., Matsumoto, W., Hashimoto, K., Izumo, S., Arimura, Y., Arimura, K., Kuriyama, M., Osame, M. pubmedImages false title Charcot-Marie-Tooth disease 1A (CMT1A) associated with a maternal duplication of chromosome 17p11.2-12. mimNumber 601097 referenceNumber 86 pubmedID 8500795 source Hum. Genet. 91: 392-394, 1993. authors Upadhyaya, M., Roberts, S. H., Farnham, J., MacMillan, J. C., Clarke, A., Heath, J. P., Hodges, I. C. G., Harper, P. S. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng1292-288 publisherName Nature Publishing Group title Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 87 publisherAbbreviation NPG pubmedID 1303281 source Nature Genet. 2: 288-291, 1992. authors Valentijn, L. J., Baas, F., Wolterman, R. A., Hoogendijk, J. E., van den Bosch, N. H. A., Zorn, I., Gabreels-Festen, A. A. W. M., de Visser, M., Bolhuis, P. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0692-166 publisherName Nature Publishing Group title The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. mimNumber 601097 referenceNumber 88 publisherAbbreviation NPG pubmedID 1303229 source Nature Genet. 1: 166-170, 1992. authors Valentijn, L. J., Bolhuis, P. A., Zorn, I., Hoogendijk, J. E., van den Bosch, N., Hensels, G. W., Stanton, V. P., Jr., Housman, D. E., Fischbeck, K. H., Ross, D. A., Nicholson, G. A., Meershoek, E. J., Dauwerse, H. G., van Ommen, G.-J. B., Baas, F. pubmedImages false publisherUrl http://www.nature.com title Dejerine-Sottas neuropathy is associated with a de novo PMP22 mutation. mimNumber 601097 referenceNumber 89 pubmedID 7728152 source Hum. Mutat. 5: 76-80, 1995. authors Valentijn, L. J., Ouvrier, R. A., van den Bosch, N. H. A., Bolhuis, P. A., Baas, F., Nicholson, G. A. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1999826 publisherName HighWire Press title Hereditary motor and sensory neuropathies. mimNumber 601097 referenceNumber 90 publisherAbbreviation HighWire pubmedID 1999826 source J. Med. Genet. 28: 1-5, 1991. authors Vance, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMT1A duplication. mimNumber 601097 referenceNumber 91 pubmedID 8105684 source Am. J. Hum. Genet. 53: 853-863, 1993. authors Wise, C. A., Garcia, C. A., Davis, S. N., Heju, Z., Pentao, L., Patel, P. I., Lupski, J. R. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1097-4547(19990815)57:4<467::AID-JNR6>3.0.CO;2-3 publisherName John Wiley & Sons, Inc. title Characterization of peripheral myelin protein 22 in zebrafish (zPMP22) suggests an early role in the development of the peripheral nervous system. mimNumber 601097 referenceNumber 92 publisherAbbreviation Wiley pubmedID 10440896 source J. Neurosci. Res. 57: 467-478, 1999. authors Wulf, P., Bernhardt, R. R., Suter, U. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title A novel frameshift mutation in PMP22 accounts for hereditary neuropathy with liability to pressure palsies. mimNumber 601097 referenceNumber 93 pubmedID 9040737 source Neurology 48: 450-452, 1997. authors Young, P., Wiebusch, H., Stogbauer, F., Ringelstein, B., Assmann, G., Funke, H. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng.399 publisherName Nature Publishing Group title The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. mimNumber 601097 referenceNumber 94 publisherAbbreviation NPG pubmedID 19543269 source Nature Genet. 41: 849-853, 2009. authors Zhang, F., Khajavi, M., Connolly, A. M., Towne, C. F., Batish, S. D., Lupski, J. R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(10)00218-1 publisherName Elsevier Science title Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. mimNumber 601097 referenceNumber 95 publisherAbbreviation ES pubmedID 20493460 source Am. J. Hum. Genet. 86: 892-903, 2010. authors Zhang, F., Seeman, P., Liu, P., Weterman, M. A. J., Gonzaga-Jauregui, C., Towne, C. F., Batish, S. D., De Vriendt, E., De Jonghe, P., Rautenstrauss, B., Krause, K.-H., Khajavi, M., Posadka, J., Vandenberghe, A., Palau, F., Van Maldergem, L., Baas, F., Timmerman, V., Lupski, J. R. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks cmgGene false mgiHumanDisease false hprdIDs 03059 nbkIDs NBK1392;;Hereditary Neuropathy with Liability to Pressure Palsies;;;NBK1205;;Charcot-Marie-Tooth Neuropathy Type 1 refSeqAccessionIDs NG_007949.1 uniGenes Hs.372031,Hs.658306 approvedGeneSymbols PMP22 nextGxDx true locusSpecificDBs http://www.molgen.ua.ac.be/CMTMutations/;;Inherited Peripheral Neuropathies Mutation Database dermAtlas false umlsIDs C1418677 gtr true geneIDs 5376 swissProtIDs Q01453 zfinIDs ZDB-GENE-060421-4337,ZDB-GENE-030131-6757 ensemblIDs ENSG00000109099,ENST00000312280 geneTests true mgiIDs MGI:97631 ncbiReferenceSequences 527317422,527317421,527317418,527317416,527317417,527317415,527317346 genbankNucleotideSequences 20413942,12041461,49456816,123998374,732431,60552861,182984,389029373,20393209,33874197,44835645,21819422,21734104,90917107,158254711,90920369,732432,31652,220009,47055074,13331302,49456860,148137124,190130,31450862,6578129,123984406,148137123,77985118,389138314,7740042,74230032,194374120,511792319 proteinSequences 24430165,49456817,123998375,60552862,31653,527317419,24430163,220010,182985,527317347,49456861,119610353,119610352,190131,119610355,33874198,119610354,123984407,158254712,266803,4505907,194374121 geneticsHomeReferenceIDs gene;;PMP22;;PMP22

entryList

entry status live allelicVariantExists true epochCreated 518079600 geneMap geneSymbols PNP, NP sequenceID 9867 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 164050 phenotypeInheritance Autosomal recessive phenotype Immunodeficiency due to purine nucleoside phosphorylase deficiency phenotypeMimNumber 613179 chromosomeLocationStart 20937537 chromosomeSort 24 chromosomeSymbol 14 mimNumber 164050 geneInheritance None confidence C mappingMethod S, D geneName Purine nucleoside phosphorylase comments centromeric to TCRA mouseMgiID MGI:3712328,MGI:97365 mouseGeneSymbol Pnp,Pnp2 computedCytoLocation 14q11.2 cytoLocation 14q13.1 transcript uc001vxo.4 chromosomeLocationEnd 20946164 chromosome 14 contributors Victor A. McKusick - updated : 9/4/2001 Victor A. McKusick - updated : 8/19/1998 Victor A. McKusick - updated : 5/5/1997 Victor A. McKusick - updated : 4/21/1997 externalLinks flybaseIDs FBgn0035348 mgiIDs MGI:3712328,MGI:97365 mgiHumanDisease false ncbiReferenceSequences 270288734 ordrDiseases 4606;;Purine nucleoside phosphorylase deficiency refSeqAccessionIDs NG_009631.1 dermAtlas false hprdIDs 01247 swissProtIDs P00491 umlsIDs C1417772 uniGenes Hs.75514 gtr true cmgGene false nextGxDx true genbankNucleotideSequences 55925941,47115150,148130933,190147,190150,511796548,76779254,190148,164694679,190149,74353767,74355300,34532549,164691931,35564,17651680,164691907,74230042,17826631,211947962,23288921,21758577 geneTests true approvedGeneSymbols PNP geneIDs 4860 proteinSequences 47115151,55925942,76779255,74353768,108935929,74355301,35565,119586862,119586863,157168362,211947963,387033,189069240,21758578 geneticsHomeReferenceIDs gene;;PNP;;PNP locusSpecificDBs http://structure.bmc.lu.se/idbase/NPbase/;;NPbase: Mutation registry for PNP deficiency clinicalSynopsisExists false mimNumber 164050 allelicVariantList allelicVariant status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894453 text In a patient with nucleoside phosphorylase deficiency ({613179}), {20:Williams et al. (1987)} identified a homozygous 265G-A transition in exon 3 of the PNP gene, resulting in a glu89-to-lys (E89K) substitution. The patient was born of consanguineous parents. mutations PNP, GLU89LYS number 1 clinvarAccessions RCV000015025;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894454 text In a patient with nucleoside phosphorylase deficiency ({613179}), {13:Markert and Barrett (1989)} identified compound heterozygosity for 2 mutations in the PNP gene: a 520G-C transversion, resulting in an ala174-to-pro (A174P) substitution, and E89K ({164050.0001}). {12:Markert (1992)} indicated that this mutant protein had normal function when expressed in COS cells. However, it was possible that the mutation may have caused an abnormality in protein stability or other posttranscriptional stages. mutations PNP, ALA174PRO number 2 clinvarAccessions RCV000015026;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894450 text In a patient with nucleoside phosphorylase deficiency ({613179}), {3:Aust et al. (1992)} found an asp128-to-gly (D128G) substitution in the maternal allele and an arg234-to-pro mutation (R234P; {164050.0004}) in the paternal allele. In addition, the patient was homozygous for a ser51-to-gly substitution (S51G; {164050.0005}), which is a polymorphism. In order to prove that the 2 mutations were responsible for the disease state, each of the 3 mutations was constructed separately by site-directed mutagenesis of the normal PNP cDNA, and each was transiently expressed in COS cells. Lysates from cells transfected with the allele carrying the substitution at amino acid 51 retained both function and immunoreactivity. Lysates from cells transfected with alleles carrying a substitution at either amino acid 128 or amino acid 234 contained immunoreactive material but had no detectable human enzyme activity. mutations PNP, ASP128GLY number 3 clinvarAccessions RCV000015027;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894451 text See {164050.0003} and {3:Aust et al. (1992)}. {14:Markert et al. (1997)} found the arg234-to-pro (R234P) mutation in 3 unrelated patients, making this the most common mutation reported in PNP deficiency to that time. mutations PNP, ARG234PRO number 4 clinvarAccessions RCV000015028;;1 status live name NUCLEOSIDE PHOSPHORYLASE POLYMORPHISM dbSnps rs1049564 text See {164050.0003} and {3:Aust et al. (1992)}. mutations PNP, SER51GLY number 5 clinvarAccessions RCV000127500;;1;;;RCV000015029;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894452 text {15:Pannicke et al. (1996)} studied a female patient with severe combined immunodeficiency ({613179}) and found compound heterozygosity for 2 mutations in the PNP gene: an A-to-G transition in exon 5, resulting in a tyr192-to-cys (Y192C) substitution, and a 1-bp deletion in exon 6 ({164050.0007}), resulting in premature termination. Both PNP mutations affected major structural motifs of the protein and resulted in posttranslational instability of the enzyme. The patient showed the first signs of developmental delay at the age of 6 months and at 20 months recurrent bronchitis and episodes of sepsis pneumonia began. At the age of 24 months, she presented with persistent diarrhea. PNP deficiency was diagnosed at 2.5 years when she developed a large lymphoma due to EBV infection. After chemotherapy, a haploidentical maternal bone marrow transplantation was performed at the age of 35 months. However, the patient died from a severe systemic adenovirus infection at 36 months. mutations PNP, TYR192CYS number 6 clinvarAccessions RCV000015030;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY text See {164050.0006} and {15:Pannicke et al. (1996)}. mutations NP, 1-BP DEL number 7 clinvarAccessions RCV000015031;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894455 text In a patient with nucleoside phosphorylase deficiency ({613179}), {18:Sasaki et al. (1998)} demonstrated homozygosity for an arg24-to-ter (R24X) substitution in exon 2. Both parents were heterozygous for the mutation. The patient, a 3-year-old boy, was the third of 3 children born of a second-cousin marriage. After birth, the patient had recurrent urinary tract infections. He showed hypouricemia, lymphopenia, an immunologic disorder in T-cell function, a low level of plasma hypoxanthine, and a high level of plasma inosine. mutations PNP, ARG24TER number 8 clinvarAccessions RCV000015032;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY dbSnps rs104894460 text In a case of PNP deficiency ({613179}), {4:Dalal et al. (2001)} found compound heterozygosity for mutations in the PNP gene, a maternally-derived arg58-to-ter (R58X) mutation and a paternally-derived splice site mutation. The maternal allele showed a 172C-T transition in exon 2, resulting in R58X. The paternally-derived allele showed complete absence of exon 3 with precise joining of exon 2 to exon 4, due to a G-to-A transition in intron 3 at position +1 (see {164050.0010}). A frameshift resulted from a change in the reading frame because of the split codon, which was GTG (val) in the normal bridge between exon 2 and exon 3, but became GGT (gly) in the bridge between exon 2 and exon 4. Translation of the mutant paternally-derived allele terminated after 89 amino acids, 29 residues downstream of the exon 2-exon 4 junction. mutations PNP, ARG58TER number 9 clinvarAccessions RCV000015033;;1 status live name NUCLEOSIDE PHOSPHORYLASE DEFICIENCY text See {164050.0009} and {4:Dalal et al. (2001)}. mutations PNP, IVS3DS, G-A, +1 number 10 clinvarAccessions RCV000015034;;1 prefix * titles alternativeTitles NUCLEOSIDE PHOSPHORYLASE; NP;; PURINE-NUCLEOSIDE:ORTHOPHOSPHATE RIBOSYLTRANSFERASE preferredTitle PURINE NUCLEOSIDE PHOSPHORYLASE; PNP textSectionList textSection textSectionTitle Description textSectionContent The PNP gene encodes purine nucleoside phosphorylase ({EC 2.4.2.1}), an enzyme that catalyzes the reversible phosphorolysis of the purine nucleosides and deoxynucleosides inosine, guanosine, deoxyinosine, and deoxyguanosine ({21:Williams et al., 1984}). textSectionName description textSectionTitle Cloning textSectionContent {22:Zannis et al. (1978)} and {21:Williams et al. (1984)} demonstrated that human PNP is a symmetric trimer composed of 3 identical 32,153-Da subunits, each with a substrate-binding site. PNP encodes a deduced protein of 289 amino acids. textSectionName cloning textSectionTitle Mapping textSectionContent From the findings in somatic cell hybridization studies, nucleoside phosphorylase is known to be determined by a structural locus on chromosome 14. In a classic experiment using the KOP (Kirby-Opitz-Pallister) cell line carrying an X;14 translocation (GM73 and GM74), {17:Ricciuti and Ruddle (1973)} showed that the PNP locus is on chromosome 14 (and G6PD ({305900}) on distal Xq). In hybridization experiments with t(X;14)(p22;q21), {7:Francke et al. (1976)} found that the PNP locus is proximal to 14q22. Using gene dosage effect and 4 cases of different partial trisomy of chromosome 14, {9:George and Francke (1976)} narrowed the assignment of PNP to the region 14q11-q21. {8:Frecker et al. (1978)} presented results from gene dosage studies consistent with assignment of the PNP locus to band 14q13. {2:Allderdice et al. (1978)} investigated spreading of inactivation in the KOP translocation originally used in mapping PNP to 14q. {16:Remes et al. (1984)} presented additional deletion mapping data that they interpreted, in the light of earlier findings, as narrowing the SRO for PNP to 14q12.00-q13.105. The location was placed at 14q13.1. The evidence of {10:Harper et al. (1988)} indicated that the PNP gene is located centromeric to TCRA (see {186880}). HGM10 concluded that PNP is located in the 14q11.2 band. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {6:Edwards et al. (1971)} described electrophoretic variants of nucleoside phosphorylase. Family studies indicated autosomal codominant inheritance of the variants. In a patient with nucleoside phosphorylase deficiency ({613179}), {20:Williams et al. (1987)} identified a homozygous mutation in the PNP gene (E89K; {164050.0001}). {3:Aust et al. (1992)} identified compound heterozygosity for 2 mutations in the PNP gene (D128G, {164050.0003}; R234P, {164050.0004}) in a patient with nucleoside phosphorylase deficiency. In a patient with PNP deficiency, {4:Dalal et al. (2001)} identified compound heterozygosity for 2 mutations in the PNP gene ({164050.0009}; {164050.0010}). textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent By male germ cell mutagenesis, {19:Snyder et al. (1997)} recovered 3 point mutations in the Pnp gene. These were, in order of increasing order of severity of enzyme deficiency and phenotype, met87 to lys, ala228 to thr, and trp16 to arg. A marked decline in total cell numbers per thymus occurred between 2 and 3 months for the 2 more severe mutants (35% and 52%, respectively) and by 8 months for the least severe mutation. Spleen lymphocyte Thy-1(+) cells were reduced by 50% and spleen lymphocyte response to T-cell mitogen and interleukin-2 was reduced by 80%. The Pnp-deficient mouse exhibited age-dependent progressive perturbations in thymocyte differentiation, reduced numbers of thymocytes, and reduced splenic T-cell numbers and response. The progressive T-cell deficit was similar to that observed in the human disorder. textSectionName animalModel geneMapExists true editHistory mgross : 10/04/2013 carol : 12/16/2009 ckniffin : 12/16/2009 carol : 12/14/2009 terry : 2/2/2009 ckniffin : 10/28/2004 joanna : 3/17/2004 alopez : 9/7/2001 terry : 9/4/2001 carol : 11/13/2000 carol : 8/24/1998 terry : 8/19/1998 mark : 5/5/1997 terry : 4/24/1997 jenny : 4/21/1997 terry : 4/15/1997 jenny : 1/10/1997 terry : 12/26/1996 mimadm : 12/2/1994 warfield : 4/12/1994 carol : 11/3/1992 carol : 10/21/1992 supermim : 3/16/1992 carol : 3/2/1992 dateCreated Mon, 02 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/2/1986 epochUpdated 1380870000 dateUpdated Fri, 04 Oct 2013 03:00:00 EDT referenceList reference title Regional assignment of nucleoside phosphorylase by exclusion to 14q13. mimNumber 164050 referenceNumber 1 pubmedID 110525 source Cytogenet. Cell Genet. 22: 490-492, 1978. authors Aitken, D. A., Ferguson-Smith, M. A. pubmedImages false title Spreading of inactivation in an (X;14) translocation. mimNumber 164050 referenceNumber 2 pubmedID 263441 source Am. J. Med. Genet. 2: 233-240, 1978. authors Allderdice, P. W., Miller, O. J., Miller, D. A., Klinger, H. P. pubmedImages false title Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. mimNumber 164050 referenceNumber 3 pubmedID 1384322 source Am. J. Hum. Genet. 51: 763-772, 1992. authors Aust, M. R., Andrews, L. G., Barrett, M. J., Norby-Slycord, C. J., Markert, M. L. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2001&volume=59&issue=6&spage=430 publisherName Blackwell Publishing title Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient. mimNumber 164050 referenceNumber 4 publisherAbbreviation Blackwell pubmedID 11453975 source Clin. Genet. 59: 430-437, 2001. authors Dalal, I., Grunebaum, E., Cohen, A., Roifman, C. M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Order of genes for NP and TRPRS on chromosome 14. mimNumber 164050 referenceNumber 5 pubmedID 110526 source Cytogenet. Cell Genet. 22: 493-497, 1978. authors Denny, R. M., Borgaonkar, D., Ruddle, F. H. pubmedImages false title Inherited variants of human nucleoside phosphorylase. mimNumber 164050 referenceNumber 6 pubmedID 5579411 source Ann. Hum. Genet. 34: 395-408, 1971. authors Edwards, Y. H., Hopkinson, D. A., Harris, H. pubmedImages false title Intrachromosomal gene mapping in man: assignment of nucleoside phosphorylase to region 14cen-to-14q21 by interspecific hybridization of cells with a t(X;14)(p22;q21) translocation. mimNumber 164050 referenceNumber 7 pubmedID 829289 source Somat. Cell Genet. 2: 27-40, 1976. authors Francke, U., Busby, N., Shaw, D., Hansen, S., Brown, M. G. pubmedImages false title Confirmation of regional assignment of nucleoside phosphorylase (NP) on chromosome 14 by gene dosage studies. mimNumber 164050 referenceNumber 8 pubmedID 216625 source Hum. Genet. 45: 167-173, 1978. authors Frecker, M., Dallaire, L., Young, S. R., Chen, G. C. C., Simpson, N. E. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=824731 publisherName HighWire Press title Gene dose effect: regional mapping of human nucleoside phosphorylase on chromosome 14. mimNumber 164050 referenceNumber 9 publisherAbbreviation HighWire pubmedID 824731 source Science 194: 851-852, 1976. authors George, D. L., Francke, U. pubmedImages false publisherUrl http://highwire.stanford.edu title Proximity of the CTLA-1 serine esterase and Tcr(alpha) loci in mouse and man. mimNumber 164050 referenceNumber 10 pubmedID 3182016 source Immunogenetics 28: 439-444, 1988. authors Harper, K., Mattei, M.-G., Simon, D., Suzan, M., Guenet, J.-L., Haddad, P., Sasportes, M., Golstein, P. pubmedImages false title Effet de dosage sesquialtere de la nucleoside phosphorylase erythrocytaire et leucocytaire dans deux cas de trisomie partielle 14q. mimNumber 164050 referenceNumber 11 pubmedID 6772087 source Ann. Genet. 23: 86-88, 1980. authors Junien, C., Kaplan, J. C., Raoul, O., Rethore, M.-O., Turleau, C., de Grouchy, J. pubmedImages false source Durham, N. C. 10/22/1992. mimNumber 164050 authors Markert, M. L. title Personal Communication. referenceNumber 12 source Am. J. Hum. Genet. 45 (suppl.): A205 only, 1989. mimNumber 164050 authors Markert, M. L., Barrett, M. J. title Point mutations causing purine nucleoside phosphorylase deficiency in a child with immunodeficiency. (Abstract) referenceNumber 13 articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:2<118::AID-HUMU3>3.0.CO;2-5 publisherName John Wiley & Sons, Inc. title Mutations in purine nucleoside phosphorylase deficiency. mimNumber 164050 referenceNumber 14 publisherAbbreviation Wiley pubmedID 9067751 source Hum. Mutat. 9: 118-121, 1997. authors Markert, M. L., Finkel, B. D., McLaughlin, T. M., Watson, T. J., Collard, H. R., McMahon, C. P., Andrews, L. G., Barrett, M. J., Ward, F. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://link.springer.de/link/service/journals/00439/bibs/6098006/60980706.htm publisherName Springer title Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. mimNumber 164050 referenceNumber 15 publisherAbbreviation Springer pubmedID 8931706 source Hum. Genet. 98: 706-709, 1996. authors Pannicke, U., Tuchschmid, P., Friedrich, W., Bartram, C. R., Schwarz, K. pubmedImages false publisherUrl http://www.springeronline.com/ source Cytogenet. Cell Genet. 37: 568 only, 1984. mimNumber 164050 authors Remes, G. M., Fisher, R. A., Hackel, E., Cousineau, A. J., Higgins, J. V. title SRO refinement for nucleoside phosphorylase by deletion mapping of chromosome 14. (Abstract) referenceNumber 16 title Assignment of nucleoside phosphorylase to D-14 and localization of X-linked loci in man by somatic cell genetics. mimNumber 164050 referenceNumber 17 pubmedID 4512579 source Nature N.B. 241: 180-182, 1973. authors Ricciuti, F., Ruddle, F. H. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/8103001/81030081.htm publisherName Springer title Direct evidence of autosomal recessive inheritance of arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient. mimNumber 164050 referenceNumber 18 publisherAbbreviation Springer pubmedID 9737781 source Hum. Genet. 103: 81-85, 1998. authors Sasaki, Y., Iseki, M., Yamaguchi, S., Kurosawa, Y., Yamamoto, T., Moriwaki, Y., Kenri, T., Sasaki, T., Yamashita, R. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9122228 publisherName HighWire Press title Point mutations at the purine nucleoside phosphorylase locus impair thymocyte differentiation in the mouse. mimNumber 164050 referenceNumber 19 publisherAbbreviation HighWire pubmedID 9122228 source Proc. Nat. Acad. Sci. 94: 2522-2527, 1997. authors Snyder, F. F., Jenuth, J. P., Mably, E. R., Mangat, R. K. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=3029074 publisherName HighWire Press title A human purine nucleoside phosphorylase deficiency caused by a single base change. mimNumber 164050 referenceNumber 20 publisherAbbreviation HighWire pubmedID 3029074 source J. Biol. Chem. 262: 2332-2338, 1987. authors Williams, S. R., Gekeler, V., McIvor, R. S., Martin, D. W., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=6087295 publisherName HighWire Press title Human purine nucleoside phosphorylase cDNA sequence and genomic clone characterization. mimNumber 164050 referenceNumber 21 publisherAbbreviation HighWire pubmedID 6087295 source Nucleic Acids Res. 12: 5779-5787, 1984. authors Williams, S. R., Goddard, J. M., Martin, D. W., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=412851 publisherName HighWire Press title Purification and characterization of human erythrocyte purine nucleoside phosphorylase and its subunits. mimNumber 164050 referenceNumber 22 publisherAbbreviation HighWire pubmedID 412851 source J. Biol. Chem. 253: 504-510, 1978. authors Zannis, V., Doyle, D., Martin, D. W., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu seeAlso Aitken and Ferguson-Smith (1978); Denny et al. (1978); Junien et al. (1980)

entryList

entry status live allelicVariantExists true epochCreated 943948800 geneMap geneSymbols B4GALT7, XGALT1, XGPT1, EDSP1 sequenceID 4518 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 604327 phenotypeInheritance Autosomal recessive phenotype Ehlers-Danlos syndrome, progeroid type, 1 phenotypeMimNumber 130070 chromosomeLocationStart 177027118 chromosomeSort 660 chromosomeSymbol 5 mimNumber 604327 geneInheritance None confidence C mappingMethod REc, A geneName Xylosylprotein 4-beta-galactosyltransferase, polypeptide 7 mouseMgiID MGI:2384987 mouseGeneSymbol B4galt7 computedCytoLocation 5q35.3 cytoLocation 5q35.2-q35.3 transcript uc003mhy.3 chromosomeLocationEnd 177037347 chromosome 5 contributors Patricia A. Hartz - updated : 11/4/2009 Marla J. F. O'Neill - updated : 7/21/2004 Carol A. Bocchini - updated : 1/8/2001 Carol A. Bocchini - updated : 12/3/1999 clinicalSynopsisExists false mimNumber 604327 allelicVariantList allelicVariant status live name EHLERS-DANLOS SYNDROME, PROGEROID TYPE, 1 dbSnps rs121917817 text In the defining case of progeroid EDS (EDSP1; {130070}) reported by {4:Kresse et al. (1987)}, {6:Okajima et al. (1999)} and {1:Almeida et al. (1999)} independently found compound heterozygosity for ala186-to-asp and leu206-to-pro ({604327.0002}) mutations in the B4GALT7 gene. The father was heterozygous for the leu206-to-pro mutation; the mother was heterozygous for the ala186-to-asp mutation. mutations B4GALT7, ALA186ASP number 1 clinvarAccessions RCV000005963;;1 status live name EHLERS-DANLOS SYNDROME, PROGEROID TYPE, 1 dbSnps rs121917818 text See {604327.0001}, {6:Okajima et al. (1999)}, and {1:Almeida et al. (1999)}. mutations B4GALT7, LEU206PRO number 2 clinvarAccessions RCV000005964;;1 status live name EHLERS-DANLOS SYNDROME, PROGEROID TYPE, 1 dbSnps rs28937869 text In 2 affected members of a large consanguineous Arab family with the progeroid type of Ehlers-Danlos syndrome (EDSP1; {130070}), {2:Faiyaz-Ul-Haque et al. (2004)} identified homozygosity for an 808C-T transition in exon 5 of the B4GALT7 gene, resulting in an arg270-to-cys (R270C) substitution in the catalytically active extracellular C-terminal domain. The authors noted that the affected members in this family exhibited somewhat milder skin changes than those previously described. {3:Gotte et al. (2008)} showed that R270C mutant fibroblasts produced heparan sulfate with a reduced level of sulfation compared with normal control fibroblasts. Altered heparan sulfate resulted in several changes of the cellular phenotype, including delayed wound repair, altered fibronectin adhesion, actin stress fiber and filopodia formation, and collagen gel contraction. mutations B4GALT7, ARG270CYS number 3 clinvarAccessions RCV000005965;;1 prefix * titles alternativeTitles XGPT1; XGALT1;; GALACTOSYLTRANSFERASE I preferredTitle XYLOSYLPROTEIN 4-BETA-GALACTOSYLTRANSFERASE, POLYPEPTIDE 7; B4GALT7 textSectionList textSection textSectionTitle Description textSectionContent Galactosyltransferase I (UDP-galactose:O-beta-D-xylosylprotein 4-beta-D-galactosyltransferase; {EC 2.4.1.133}) is involved in the synthesis of the glycosaminoglycan-protein linkage in proteoglycans ({7:Okajima et al., 1999}). textSectionName description textSectionTitle Cloning textSectionContent By searching an EST database for orthologs of C. elegans sqv3, followed by RT-PCR of a colon cancer cDNA library and 5-prime RACE, {7:Okajima et al. (1999)} cloned human BGALT7, which encodes xylosylprotein 4-beta-galactosyltransferase. The deduced 327-amino acid protein has a calculated molecular mass of 37.4 kD. B4GALT7 has a hydrophobic segment in its N-terminal region, predicting that the protein assumes a type II transmembrane topology. It also has 1 N-glycosylation site. textSectionName cloning textSectionTitle Gene Structure textSectionContent {1:Almeida et al. (1999)} determined that the B4GALT7 gene contains 6 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {1:Almeida et al. (1999)} found that ESTs from B4GALT7 matched sequences in a Unigene cluster (Hs.45208) that had been mapped to chromosome 5q35.1-q35.3. By fluorescence in situ hybridization, {5:Kuroiwa et al. (2000)} assigned the B4GALT7 gene to 5q35.2-q35.3. textSectionName mapping textSectionTitle Gene Function textSectionContent Using a variety of possible galactose acceptor substrates, {7:Okajima et al. (1999)} showed that human B4GALT7 expressed in mouse fibroblasts had significant activity with p-nitrophenyl-beta-D-xylopyranoside, a primer for glycosaminoglycan chain formation. Characterization of the product revealed that galactose was added via beta-1,4 linkage. In the progeroid type of Ehlers-Danlos syndrome ({130070}), {4:Kresse et al. (1987)} found deficiency of galactosyltransferase I (xylosylprotein 4-beta-galactosyltransferase). textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {6:Okajima et al. (1999)} and {1:Almeida et al. (1999)} independently performed mutation analysis of the B4GALT7 gene in fibroblasts from the patient with progeroid Ehlers-Danlos syndrome (EDSP1; {130070}) reported by {4:Kresse et al. (1987)}. They found that the patient was compound heterozygous for 2 mutations in the XGPT1 gene ({604327.0001}-{604327.0002}), which were present in the mother and the father, respectively. In 2 affected members of a large consanguineous Arab family with the progeroid form of Ehlers-Danlos syndrome, {2:Faiyaz-Ul-Haque et al. (2004)} identified a homozygous arg270-to-cys mutation in the B4GALT7 gene (R270C; {604327.0003}). textSectionName molecularGenetics geneMapExists true editHistory carol : 08/01/2013 mgross : 11/12/2009 carol : 11/10/2009 carol : 11/6/2009 terry : 11/4/2009 tkritzer : 7/23/2004 terry : 7/21/2004 carol : 11/24/2001 cwells : 1/9/2001 carol : 1/8/2001 carol : 12/3/1999 carol : 12/1/1999 carol : 12/1/1999 dateCreated Tue, 30 Nov 1999 03:00:00 EST creationDate Victor A. McKusick : 11/30/1999 epochUpdated 1375340400 dateUpdated Thu, 01 Aug 2013 03:00:00 EDT referenceList reference articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10473568 publisherName HighWire Press title Cloning and expression of a proteoglycan UDP-galactose:beta-xylose beta-1,4-galactosyltransferase I: a seventh member of the human beta4-galactosyltransferase gene family. mimNumber 604327 referenceNumber 1 publisherAbbreviation HighWire pubmedID 10473568 source J. Biol. Chem. 274: 26165-26171, 1999. authors Almeida, R., Levery, S. B., Mandel, U., Kresse, H., Schwientek, T., Bennett, E. P., Clausen, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.30005 publisherName John Wiley & Sons, Inc. title A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. mimNumber 604327 referenceNumber 2 publisherAbbreviation Wiley pubmedID 15211654 source Am. J. Med. Genet. 128A: 39-45, 2004. authors Faiyaz-Ul-Haque, M., Zaidi, S. H. E., Al-Ali, M., Al-Mureikhi, M. S., Kennedy, S., Al-Thani, G., Tsui, L.-C., Teebi, A. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18158310 publisherName HighWire Press title Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (beta-4-GalT-7) deficient form of Ehlers-Danlos syndrome. mimNumber 604327 referenceNumber 3 publisherAbbreviation HighWire pubmedID 18158310 source Hum. Molec. Genet. 17: 996-1009, 2008. authors Gotte, M., Spillmann, D., Yip, G. W., Versteeg, E., Echtermeyer, F. G., van Kuppevelt, T. H., Kiesel, L. pubmedImages false publisherUrl http://highwire.stanford.edu title Glycosaminoglycan-free small proteoglycan core protein is secreted by fibroblasts from a patient with a syndrome resembling progeroid. mimNumber 604327 referenceNumber 4 pubmedID 3631078 source Am. J. Hum. Genet. 41: 436-453, 1987. authors Kresse, H., Rosthoj, S., Quentin, E., Hollmann, J., Glossl, J., Okada, S., Tonnesen, T. pubmedImages false articleUrl http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=ccg89008 publisherName S. Karger AG, Basel, Switzerland title Assignment of human xylosylprotein beta-1,4-galactosyltransferase gene (B4GALT7) to human chromosome 5q35.2-q35.3 by in situ hybridization. mimNumber 604327 referenceNumber 5 publisherAbbreviation Karger pubmedID 10894925 source Cytogenet. Cell Genet. 89: 8-9, 2000. authors Kuroiwa, A., Matsuda, Y., Okajima, T., Furukawa, K. pubmedImages false publisherUrl http://www.karger.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10506123 publisherName HighWire Press title Molecular basis for the progeroid variant of Ehlers-Danlos syndrome: identification and characterization of two mutations in galactosyltransferase I gene. mimNumber 604327 referenceNumber 6 publisherAbbreviation HighWire pubmedID 10506123 source J. Biol. Chem. 274: 28841-28844, 1999. authors Okajima, T., Fukumoto, S., Furukawa, K., Urano, T., Furukawa, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10438455 publisherName HighWire Press title Human homolog of Caenorhabditis elegans sqv-3 gene is galactosyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. mimNumber 604327 referenceNumber 7 publisherAbbreviation HighWire pubmedID 10438455 source J. Biol. Chem. 274: 22915-22918, 1999. authors Okajima, T., Yoshida, K., Kondo, T., Furukawa, K. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks flybaseIDs FBgn0039258 mgiIDs MGI:2384987 mgiHumanDisease false ncbiReferenceSequences 530380830,262231741 refSeqAccessionIDs NG_015977.1 dermAtlas false hprdIDs 05060 swissProtIDs Q9UBV7 zfinIDs ZDB-GENE-040727-3 uniGenes Hs.455109 gtr true cmgGene false ensemblIDs ENSG00000027847,ENST00000029410 umlsIDs C1412725 genbankNucleotideSequences 71514336,34528557,511815910,5921264,123991241,148158714,6651189,40034099,10434029,37182277,5738914,33873618,21755228,47940492,126634837,28933571,38614454,10435458,123999386 geneTests true approvedGeneSymbols B4GALT7 geneIDs 11285 proteinSequences 530380831,123991242,193785766,5921265,193788263,578810994,578810992,37182278,6651190,5738915,13938368,40034100,193785658,47940493,126634838,119605371,38614455,119605370,6005952,13123990,123999387 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 792921600 geneMap geneSymbols TTPA, TTP1, AVED sequenceID 6415 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 600415 phenotypeInheritance Autosomal recessive phenotype Ataxia with isolated vitamin E deficiency phenotypeMimNumber 277460 chromosomeLocationStart 63972046 chromosomeSort 256 chromosomeSymbol 8 mimNumber 600415 geneInheritance None confidence C mappingMethod Fd, LD, REc, A, REa geneName Tocopherol, alpha, transfer protein mouseMgiID MGI:1354168 mouseGeneSymbol Ttpa computedCytoLocation 8q12.3 cytoLocation 8q13.1-q13.3 transcript uc003xux.2 chromosomeLocationEnd 63998611 chromosome 8 contributors Ada Hamosh - updated : 07/07/2014 Patricia A. Hartz - updated : 7/6/2007 Cassandra L. Kniffin - updated : 2/13/2003 Victor A. McKusick - updated : 1/16/2001 Victor A. McKusick - updated : 4/2/1999 Victor A. Mckusick - updated : 4/18/1998 Orest Hurko - updated : 5/6/1996 clinicalSynopsisExists false mimNumber 600415 allelicVariantList allelicVariant status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs397515377 text In 68% of the mutant alleles in 17 families with AVED ({277460}), {7:Ouahchi et al. (1995)} found a deletion of 1 bp (A) at position 744. The mutation, referred to as Mediterranean, appeared to have spread in North Africa and Italy. mutations TTPA, 1-BP DEL number 1 clinvarAccessions RCV000009707;;1;;;RCV000055806;;1 status live name ATAXIA AND RETINITIS PIGMENTOSA WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs121917849 text {4:Gotoda et al. (1995)} found a missense mutation in the TTP1 gene in a 70-year-old man who had been well until the age of 52 years when he became aware of unsteadiness in the dark. At the age of 57, he began to have difficulty speaking. Thereafter ataxia and dysarthria progressed very slowly. At the age of 62 years, he was found to have extremely low serum vitamin E concentrations ({13:Yokota et al., 1987}); his parents and children, all of whom were neurologically normal, were found to have concentrations that were low or below normal. Improvement or stabilization of his neurologic dysfunction and symptoms occurred with administration of large doses of alpha-tocopherol acetate. The man came from a small, isolated island located 290 km from the mainland of Japan, where his family had lived for many generations. The proband was found to be homozygous for a T-to-G transversion at nucleotide 303 of the TTP1 cDNA, predicted to result in replacement of histidine (CAT) with glutamine (CAG) as residue 101. The his101-to-gln substitution could be detected by the fact that it disrupted a restriction site for NcoI. A mutant allele was not detected in 150 unrelated Japanese subjects living in Tokyo; however, of 801 island inhabitants, 21 were heterozygous for the his101-to-gln mutation. All 21 were asymptomatic and had normal physical examinations, and none was known to be related to the patient. On the average, heterozygotes had serum vitamin E concentrations 25% lower than those in normal subjects. {12:Yokota et al. (1996)} demonstrated that retinitis pigmentosa is also a feature of this mutation. mutations TTPA, HIS101GLN number 2 clinvarAccessions RCV000009708;;1;;;RCV000055795;;1 status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs397515378 text {5:Hentati et al. (1996)} found a severely affected patient with ataxia and peripheral neuropathy ({277460}) who had deletion of nucleotide 485 in the TTPA gene. The deletion resulted in a frameshift and generation of a premature stop codon at residue 176. mutations TTPA, 1-BP DEL, 485T number 3 clinvarAccessions RCV000055799;;1;;;RCV000009709;;1 status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs397515379 text {5:Hentati et al. (1996)} found a patient severely affected with ataxia and peripheral neuropathy ({277460}) who was homozygous for insertion of 2 thymine residues at nucleotide position 513 of their TTPA sequence, causing a frameshift and a premature stop codon. mutations TTPA, 2-BP INS, 513TT number 4 clinvarAccessions RCV000055800;;1;;;RCV000009710;;1 status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs121917850 text {5:Hentati et al. (1996)} found a mildly affected patient with vitamin E deficiency ({277460}) who was a compound heterozygote for a 574G-A point mutation resulting in an arg192-to-his amino acid substitution, and the 513insTT TT mutation ({600415.0004}). mutations TTPA, ARG192HIS number 5 clinvarAccessions RCV000055803;;1;;;RCV000009711;;1 status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY dbSnps rs121917851 text In 2 independent Canadian families with AVED ({277460}), {2:Cavalier et al. (1998)} found a truncating arg134-to-ter mutation in homozygous state in 1 patient with consanguineous parents and in compound heterozygous state with the 486delT mutation in the second nonconsanguineous family. mutations TTPA, ARG134TER number 6 clinvarAccessions RCV000009712;;1;;;RCV000055797;;1 status live name ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY text In a patient with ataxia and vitamin E deficiency ({277460}), {9:Schuelke et al. (1999)} identified a homozygous 552G-A mutation in the TTPA gene. Both parents were heterozygous for the mutation. The mutation did not cause an exchange of amino acids, but at the mRNA level, {9:Schuelke et al. (1999)} demonstrated that its position within a splice donor site led to abnormal splicing. Because liver tissue was not available for mRNA preparation, the authors amplified illegitimate transcripts from lymphoblastoid cells. In all mRNA transcripts, exon 3 was missing. In both parents, they detected both intact and truncated mRNA copies. The missplicing caused a shift in the reading frame with an aberrant amino acid sequence from codon 120 onward to a premature stop at codon 134. The truncated protein completely lacked the domains encoded by exons 3 to 5. mutations TTPA, 552G-A number 7 clinvarAccessions RCV000009713;;1 prefix * titles alternativeTitles TTP1;; ALPHA-TOCOPHEROL TRANSFER PROTEIN; ATTP;; ALPHA-TTP preferredTitle TOCOPHEROL TRANSFER PROTEIN, ALPHA; TTPA textSectionList textSection textSectionTitle Cloning textSectionContent Using rat alpha-Ttp to screen a liver cDNA library, followed by PCR, {1:Arita et al. (1995)} cloned full-length human alpha-TTP. The deduced 278-amino acid protein has a calculated molecular mass of 31.7 kD and shares 94% identity with rat alpha-Ttp. Northern blot analysis of several human tissues detected a 4.5-kb alpha-TTP transcript in liver only. textSectionName cloning textSectionTitle Gene Function textSectionContent {1:Arita et al. (1995)} found that recombinant human alpha-TTP transferred alpha-tocopherol from liposomes to the heavy membrane fraction. {6:Kono et al. (2013)} found that wildtype TTPA bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants that cause ataxia with vitamin E deficiency in humans did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of alpha-tocopherol by TTPA. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent Crystal Structure {6:Kono et al. (2013)} determined the crystal structure of the TTPA-PIP complex, which revealed that disease-related arginine residues interacted with the phosphate groups of the PIPs and that the PIPs' binding caused the lid of the alpha-tocopherol-binding pocket to open. {6:Kono et al. (2013)} concluded that PIPs have a role in promoting the release of a ligand from a lipid transfer protein. textSectionName biochemicalFeatures textSectionTitle Mapping textSectionContent By Southern blot hybridization of human/hamster somatic cell hybrid lines and fluorescence in situ hybridization, {1:Arita et al. (1995)} identified a single TTP1 gene in the chromosome 8q13.1-q13.3 region. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent The role of TTP1 in vitamin E homeostasis, coupled with the mapping of ataxia with isolated vitamin E deficiency (AVED; {277460}) also to 8q, prompted {7:Ouahchi et al. (1995)} to investigate a possible role of the TTP1 gene in that disorder. A mutation search of the TTP1 gene was made in 17 unrelated AVED families. In 15 families, the patients were homozygous for the linked haplotype, in agreement with known consanguinity in 12 cases and suggesting ancient consanguinity in the 3 remaining ones. In 68% of the mutant alleles in the 17 families analyzed, deletion of a single A at position 744 was found to have resulted in the replacement of the last 30 amino acids of the protein product by an aberrant 14 amino acid peptide. The mutation was referred to as Mediterranean because it appeared to have spread in North Africa and Italy. Two other independent frameshift mutations were found in patients of northern European ancestry. {8:Robinson et al. (1982)} found in experiments in animals that diets deficient in vitamin E cause retinitis pigmentosa. For this reason, {12:Yokota et al. (1996)} studied the TTPA gene in 2 unrelated patients, a 60-year-old woman (patient 1) and a 47-year-old man (patient 2), who had autosomal recessive retinitis pigmentosa and low serum vitamin E concentrations. In both patients they found a his101-to-gln mutation ({600415.0002}). Initial visual symptoms were night blindness in patient 1, which began at the age of 43 years, and loss of peripheral vision in patient 2, which began at the age of 45 years. This patient also had mild ataxia, decreased vibration sense, and hyporeflexia. In each, ophthalmoscopy showed the typical changes for retinitis pigmentosa, Goldmann perimetry revealed a ring scotoma, and electroretinography showed no light-evoked electrical responses. {2:Cavalier et al. (1998)} reported identification of 13 mutations in the TTPA gene in 27 families with AVED. Four mutations were found in 2 or more independent families: 744delA ({600415.0001}), which is the major mutation in North Africa, and 513insTT, 486delT, and arg134 to ter, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the TTPA gene revealed differences from Friedreich ataxia ({229300}): cardiomyopathy was found in 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represented the largest group of patients and mutations reported for this often misdiagnosed disease and pointed to the need for an early differential diagnosis from Friedreich ataxia in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops. {3:Cellini et al. (2002)} reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 ({608768}) and also had compound heterozygosity for mutations in the TTPA gene ({600415.0004} and {600415.0006}), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. {3:Cellini et al. (2002)} suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Although lipid peroxidation in the subendothelial space had been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remained uncertain. {10:Terasawa et al. (2000)} showed that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the alpha-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. Ttpa -/- mice present a useful genetic model of vitamin E deficiency. Using differential analysis, {11:Vasu et al. (2007)} compared gene expression in heart tissue of Attp -/- mice with that of wildtype mice. Of the 65 genes affected by Attp deletion, a cluster of genes related to immune function were downregulated, whereas genes related to lipid metabolism and inflammatory response were upregulated. Classic antioxidant genes showed no significant change in expression in Attp -/- mice. textSectionName animalModel geneMapExists true editHistory alopez : 07/07/2014 mgross : 7/27/2007 terry : 7/6/2007 carol : 7/2/2004 carol : 2/24/2003 ckniffin : 2/13/2003 mcapotos : 1/25/2001 mcapotos : 1/23/2001 terry : 1/16/2001 carol : 5/18/1999 carol : 4/2/1999 mgross : 4/2/1999 carol : 4/18/1998 terry : 3/27/1998 mark : 9/1/1997 jamie : 2/12/1997 jamie : 1/8/1997 mark : 1/6/1997 terry : 1/3/1997 mark : 5/6/1996 mark : 5/6/1996 terry : 2/6/1996 mark : 12/8/1995 terry : 12/8/1995 mimadm : 9/23/1995 terry : 7/10/1995 mark : 6/13/1995 terry : 4/20/1995 carol : 2/16/1995 dateCreated Thu, 16 Feb 1995 03:00:00 EST creationDate Victor A. McKusick : 2/16/1995 epochUpdated 1404716400 dateUpdated Mon, 07 Jul 2014 03:00:00 EDT referenceList reference title Human alpha-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. mimNumber 600415 referenceNumber 1 pubmedID 7887897 source Biochem. J. 306: 437-443, 1995. authors Arita, M., Sato, Y., Miyata, A., Tanabe, T., Takahashi, E., Kayden, H. J., Arai, H., Inoue, K. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63495-8 publisherName Elsevier Science title Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. mimNumber 600415 referenceNumber 2 publisherAbbreviation ES pubmedID 9463307 source Am. J. Hum. Genet. 62: 301-310, 1998. authors Cavalier, L., Ouahchi, K., Kayden, H. J., Di Donato, S., Reutenauer, L., Mandel, J.-L., Koenig, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=12470185 publisherName HighWire Press title A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. mimNumber 600415 referenceNumber 3 publisherAbbreviation HighWire pubmedID 12470185 source Arch. Neurol. 59: 1952-1953, 2002. authors Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199511163332003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. mimNumber 600415 referenceNumber 4 publisherAbbreviation ATYPON pubmedID 7566022 source New Eng. J. Med. 333: 1313-1318, 1995. authors Gotoda, T., Arita, M., Arai, H., Inoue, K., Yokota, T., Fukuo, Y., Yazaki, Y., Yamada, N. pubmedImages false publisherUrl http://www.atypon.com/ title Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. mimNumber 600415 referenceNumber 5 pubmedID 8602747 source Ann. Neurol. 39: 295-300, 1996. authors Hentati, A., Deng, H.-X., Hung, W.-Y., Nayer, M., Ahmed, M. S., He, X., Tim, R., Stumpf, D. A., Siddique, T. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=23599266 publisherName HighWire Press title Impaired alpha-TTP-PIPs interaction underlies familial vitamin E deficiency. mimNumber 600415 referenceNumber 6 publisherAbbreviation HighWire pubmedID 23599266 source Science 340: 1106-1110, 2013. authors Kono, N., Ohto, U., Hiramatsu, T., Urabe, M., Uchida, Y., Satow, Y., Arai, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0295-141 publisherName Nature Publishing Group title Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. mimNumber 600415 referenceNumber 7 publisherAbbreviation NPG pubmedID 7719340 source Nature Genet. 9: 141-145, 1995. authors Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol, R., Arai, H., Inoue, K., Mandel, J.-L., Koenig, M. pubmedImages false publisherUrl http://www.nature.com title The role of vitamin E and unsaturated fatty acids in the visual process. mimNumber 600415 referenceNumber 8 pubmedID 6101134 source Retina 2: 263-281, 1982. authors Robinson, W. G., Kuwabara, T., Bieri, J. G. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(99)70424-5 publisherName Elsevier Science title Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency. mimNumber 600415 referenceNumber 9 publisherAbbreviation ES pubmedID 9931538 source J. Pediat. 134: 240-244, 1999. authors Schuelke, M., Mayatepek, E., Inter, M., Becker, M., Pfeiffer, E., Speer, A., Hubner, C., Finckh, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11095717 publisherName HighWire Press title Increased atherosclerosis in hyperlipidemic mice deficient in alpha-tocopherol transfer protein and vitamin E. mimNumber 600415 referenceNumber 10 publisherAbbreviation HighWire pubmedID 11095717 source Proc. Nat. Acad. Sci. 97: 13830-13834, 2000. authors Terasawa, Y., Ladha, Z., Leonard, S. W., Morrow, J. D., Newland, D., Sanan, D., Packer, L., Traber, M. G., Farese, R. V., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(07)00271-2 publisherName Elsevier Science title Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP-/-). mimNumber 600415 referenceNumber 11 publisherAbbreviation ES pubmedID 17382327 source FEBS Lett. 581: 1572-1578, 2007. authors Vasu, V. T., Hobson, B., Gohil, K., Cross, C. E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199612053352315?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol-transfer protein. (Letter) mimNumber 600415 referenceNumber 12 publisherAbbreviation ATYPON pubmedID 8965888 source New Eng. J. Med. 335: 1770-1771, 1996. authors Yokota, T., Shiojiri, T., Gotoda, T., Arai, H. pubmedImages false publisherUrl http://www.atypon.com/ title Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. mimNumber 600415 referenceNumber 13 pubmedID 3477125 source Ann. Neurol. 22: 84-87, 1987. authors Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T., Watabiki, S. pubmedImages false externalLinks mgiIDs MGI:1354168 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 262359924 nbkIDs NBK1241;;Ataxia with Vitamin E Deficiency dermAtlas false hprdIDs 02685 swissProtIDs P49638 zfinIDs ZDB-GENE-030131-4631 uniGenes Hs.69049 refSeqAccessionIDs NG_016123.1 gtr true cmgGene false ensemblIDs ENSG00000137561,ENST00000260116 umlsIDs C1421223 genbankNucleotideSequences 37046647,71517568,511809476,27697134,22091355,699600,312151169,148150330,726181 geneTests true approvedGeneSymbols TTPA geneIDs 7274 proteinSequences 119607269,578815703,312151170,699601,37046648,726182,1351322,4507723 geneticsHomeReferenceIDs gene;;TTPA;;TTPA

entryList

entry status live allelicVariantExists true epochCreated 1079510400 geneMap geneSymbols VHL sequenceID 2497 phenotypeMapList phenotypeMap phenotypeMimNumber 263400 mimNumber 608537 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 133100 phenotypeMappingKey 3 phenotype Erythrocytosis, familial, 2 phenotypeMappingKey 3 mimNumber 608537 phenotypeInheritance None phenotype Hemangioblastoma, cerebellar, somatic phenotypeMappingKey 3 mimNumber 608537 phenotypeInheritance Autosomal dominant phenotype Pheochromocytoma phenotypeMimNumber 171300 phenotypeMappingKey 3 mimNumber 608537 phenotypeInheritance None phenotype Renal cell carcinoma, somatic phenotypeMimNumber 144700 phenotypeMappingKey 3 mimNumber 608537 phenotypeInheritance Autosomal dominant phenotype von Hippel-Lindau syndrome phenotypeMimNumber 193300 chromosomeLocationStart 10183318 chromosomeSort 43 chromosomeSymbol 3 mimNumber 608537 geneInheritance None confidence C mappingMethod Fd, D, RE geneName VHL gene mouseMgiID MGI:103223 mouseGeneSymbol Vhl computedCytoLocation 3p25.3 cytoLocation 3p26-p25 transcript uc003bvc.3 chromosomeLocationEnd 10195353 chromosome 3 contributors Cassandra L. Kniffin - updated : 8/3/2011 Cassandra L. Kniffin - updated : 10/28/2010 Cassandra L. Kniffin - updated : 8/30/2010 Cassandra L. Kniffin - updated : 12/15/2009 Ada Hamosh - updated : 6/16/2009 Patricia A. Hartz - updated : 6/8/2009 Patricia A. Hartz - updated : 4/1/2009 Patricia A. Hartz - updated : 5/28/2008 Cassandra L. Kniffin - updated : 3/13/2008 Patricia A. Hartz - updated : 1/14/2008 Patricia A. Hartz - updated : 8/1/2007 Cassandra L. Kniffin - updated : 11/1/2006 Cassandra L. Kniffin - updated : 8/14/2006 Patricia A. Hartz - updated : 6/13/2006 Cassandra L. Kniffin - updated : 5/23/2006 Cassandra L. Kniffin - updated : 4/17/2006 Victor A. McKusick - updated : 3/28/2006 Cassandra L. Kniffin - updated : 1/6/2006 Victor A. McKusick - updated : 9/30/2004 Victor A. McKusick - updated : 8/24/2004 Cassandra L. Kniffin - updated : 6/2/2004 externalLinks mgiIDs MGI:103223 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 319655737,319655736 nbkIDs NBK1463;;Von Hippel-Lindau Disease dermAtlas false hprdIDs 01905 swissProtIDs P40337 zfinIDs ZDB-GENE-070112-1042 uniGenes Hs.517792 refSeqAccessionIDs NG_008212.3 gtr true cmgGene false umlsIDs C0694897 genbankNucleotideSequences 1226002,2014302,311643666,164689745,20379767,311643668,18812888,1293146,5876373,964636,71518807,164696583,37573994,306847,511857569,511857575,14294527,511857572,148171774,13036461,2282063,24418053,13043956,194384291,27830495,3523272 geneTests true approvedGeneSymbols VHL geneIDs 7428 proteinSequences 311643667,118599921,1235543,311643669,1293147,4033778,189055157,2282064,194384292,119584468,119584469,119584470,37573995,38045906,119584471,4507891,119584472 geneticsHomeReferenceIDs gene;;VHL;;VHL locusSpecificDBs http://www.umd.be/VHL/;;The UMD VHL mutations database clinicalSynopsisExists false mimNumber 608537 allelicVariantList allelicVariant status live name VON HIPPEL-LINDAU SYNDROME text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the ILE146DEL mutation has been renumbered as ILE75DEL. In a patient with von Hippel-Lindau syndrome ({193300}), {52:Latif et al. (1993)} identified an in-frame 3-nucleotide deletion at nucleotide 434 of the VHL gene, predicted to remove isoleucine-146 in the gene product. mutations VHL, 3-BP DEL, ILE75DEL number 1 clinvarAccessions RCV000002298;;1 status live name RENAL CELL CARCINOMA, SOMATIC dbSnps rs5030823 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the SER254TER mutation has been renumbered as SER183TER (S183X). In a cell line from a sporadic case of renal cell carcinoma ({144700}), {52:Latif et al. (1993)} identified a 761C-A transversion in the VHL gene, predicted to result in a ser254-to-ter (S254X) substitution. mutations VHL, SER183TER number 2 clinvarAccessions RCV000002299;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030820 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the ARG238TRP mutation has been renumbered as ARG167TRP (R167W). In a study of 94 VHL ({193300}) patients without large deletions, {17:Crossey et al. (1994)} found that the 2 most frequent mutations were missense mutations at codon 238: 4 kindreds had a 712C-T transition, resulting in an arg238-to-trp (R238W) change, and 5 kindreds had a 713G-A transition, leading to an arg238-to-gln (R238Q; {608537.0005}) substitution. Another mutation 712C-G transversion, resulting in an arg238-to-gly (R238G) substitution ({608537.0004}). All 3 mutations at codon 238 occurred at a CpG dinucleotide. The authors noted that although pheochromocytoma occurs in only about 7% of patients with VHL, a codon 238 mutation carried a high risk (62%) of pheochromocytoma. The R238W mutation was found by {28:Garcia et al. (1997)} in a Spanish family in which VHL was manifested predominantly as familial pheochromocytoma in 2 generations, consistent with VHL syndrome type 2C. In a mother and 2 sons with pheochromocytoma ({171300}), consistent with VHL syndrome type 2C, {16:Crossey et al. (1995)} identified the R238W mutation. {104:Zbar et al. (1996)} confirmed previous observations that germline codon 167 mutations of the VHL gene (R167W and R167Q; {608537.0005}) convey a high risk for the development of pheochromocytoma and renal cell carcinoma. In 21 of 33 families with mutations at codon 167, pheochromocytoma occurred, compared to 15 of 223 families without a mutation at codon 167. The association between codon 167 mutations and pheochromocytoma was detected in all nationalities tested. Two of 4 Japanese VHL pheochromocytoma families had mutations at codon 167; and 3 of 10 French VHL pheochromocytoma families had mutations at codon 167. {65:Neumann et al. (2002)} identified the R167Q substitution in the germline of a patient with sporadic pheochromocytoma ({171300}). In the germlines of 6 unrelated patients with sporadic pheochromocytoma ({171300}), {65:Neumann et al. (2002)} identified the R167W substitution. The mutation was not identified in 600 control chromosomes. mutations VHL, ARG167TRP number 3 alternativeNames PHEOCHROMOCYTOMA, INCLUDED clinvarAccessions RCV000002302;;1;;;RCV000002303;;1;;;RCV000132159;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030820 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the ARG238GLY mutation has been renumbered as ARG167GLY (R167G). See {608537.0003} and {17:Crossey et al. (1994)}. mutations VHL, ARG167GLY number 4 clinvarAccessions RCV000002304;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030821 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the ARG238GLN mutation has been renumbered as ARG167GLN (R167Q). See {608537.0003} and {17:Crossey et al. (1994)}. mutations VHL, ARG167GLN number 5 clinvarAccessions RCV000002300;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030818 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the ARG232TER mutation has been renumbered as ARG161TER (R161X). In a patient with von Hippel-Lindau syndrome ({193300}), {56:Loeb et al. (1994)} identified a 694C-T transition in exon 3 of the VHL gene, resulting in an amber stop codon arg232-to-ter (R232X). {30:Gilcrease et al. (1995)} found the identical 694C-T transition as a somatic mutation in a clear cell papillary cystadenoma of the epididymis in a patient who showed no evidence of von Hippel-Lindau syndrome and in whom somatic cells did not contain this mutation. mutations VHL, ARG161TER number 6 clinvarAccessions RCV000002301;;2;;;RCV000036547;;1 status live name HEMANGIOBLASTOMA, SPORADIC CEREBELLAR dbSnps rs119103277 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the TRP159SER mutation has been renumbered as TRP88SER (W88S). In 13 sporadic cases of cerebellar hemangioblastoma, {47:Kanno et al. (1994)} sought somatic mutations in the VHL gene with single-strand conformation polymorphism analyses of the tumor DNAs. An abnormal SSCP pattern was detected in 7, and in 3 of these the mutation was successfully characterized by direct sequencing. The somatic mutations were 2 missense mutations and 1 deletion of a single base. One of the missense mutations was a 476G-C transversion, resulting in a trp-to-ser change. The codon number was not noted. In a Japanese patient with VHL ({193300}), the {14:Clinical Research Group for VHL in Japan (1995)} identified the 476G-C transversion, which resulted in a trp159-to-ser (W159S) substitution. mutations VHL, TRP88SER number 7 alternativeNames VON HIPPEL-LINDAU SYNDROME, INCLUDED clinvarAccessions RCV000002306;;1;;;RCV000002305;;1 status live name HEMANGIOBLASTOMA, SPORADIC CEREBELLAR dbSnps rs119103278 text In a sporadic case of cerebellar hemangioblastoma, {47:Kanno et al. (1994)} identified a missense mutation in exon 2 of the VHL gene: a 618A-C transversion, resulting in a leu135-to-phe substitution. mutations VHL, LEU135PHE number 8 clinvarAccessions RCV000002307;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030809 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the TYR169HIS mutation has been renumbered as TYR98HIS (Y98H), resulting from a 292T-C transition. In 14 apparently unrelated von Hippel-Lindau syndrome type 2A ({193300}) families from the Black Forest region of Germany, {9:Brauch et al. (1995)} found a 505T-C transition in the VHL gene, resulting in a tyr169-to-his (Y169H) substitution. {9:Brauch et al. (1995)} suggested that more than 75 VHL germline mutations had been identified in VHL patients to that date. The same mutation, associated with pheochromocytoma, had been identified by {11:Chen et al. (1995)} in 2 VHL 2A families in Pennsylvania. All affected individuals in the 16 families shared the same VHL haplotype, indicating a founder effect. In at least one of the Pennsylvania families, the Y169H mutation probably derived from their Pfalz ancestors, who were among Germans who migrated to Pennsylvania. In a patient with the Y169H mutation as the cause of VHL, {85:Schimke et al. (1998)} found a functioning carotid paraganglioma. {2:Allen et al. (2001)} performed a longitudinal clinical study and DNA analysis of 24 family members, 16 of whom exhibited a 505T-C change in exon 1 of the VHL gene. Two of the 16 were asymptomatic carriers of the 505T-C mutation. Twelve of 16 (75%) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angiomas. Five gene carriers (31%) lost vision because of ocular angiomatosis. Four patients (25%) had cerebellar hemangioblastomas and 11 patients (69%) had pheochromocytomas. No patient had renal cell carcinoma, consistent with the clinical diagnosis of VHL syndrome type 2A. The authors stated that recognition of the VHL syndrome 2A phenotype suggested the presence of a specific mutation (505T-C) in the VHL gene. They suggested that confirmation of this genotype would increase a clinician's ability to provide favorable prognostic information to affected family members. {5:Bender et al. (2001)} studied 125 individuals in southern Germany carrying the 505T-C mutation. Forty-seven percent had pheochromocytoma; 36% had retinal angioma; 36%, hemangioblastoma of the spine; and 16% had hemangioblastoma of the brain. Forty-seven percent of patients were symptomatic; 30% were asymptomatic despite the presence of at least 1 VHL-related tumor; and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who died, 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence was estimated at 48% by 35 years and 88% by 70 years. {5:Bender et al. (2001)} suggested that the mortality rate for those carrying this mutation was much lower than in unselected VHL mutations and was comparable to that of the general population of Germany. mutations VHL, TYR98HIS number 9 clinvarAccessions RCV000002309;;1 status moved number 10 name MOVED TO 608537.0003 movedTo 608537.0003 status moved number 11 name MOVED TO 608537.0003 movedTo 608537.0003 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs104893824 text In a large VHL ({193300}) family with pheochromocytoma without renal carcinoma (VHL type 2A) studied by {89,90:Tisherman et al. (1962, 1993)}, {104:Zbar et al. (1996)} identified a tyr112-to-his (Y112H) mutation in the VHL gene. Of 22 affected family members, 19 were affected with pheochromocytoma; no affected family member had renal cell carcinoma. In the original report ({89:Tisherman et al., 1962}), at least 7 persons had pheochromocytoma. One or more cafe-au-lait spots (in 22 persons), extensive hemangiomas (in 2 persons), and angiomatosis retinae (in 2 persons) were discovered in the family. mutations VHL, TYR112HIS number 12 clinvarAccessions RCV000002308;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs104893825 text In a family with VHL ({193300}), {34:Gross et al. (1996)} identified a val166-to-phe (V166F) mutation in the VHL gene. Seven members had pheochromocytoma, all without renal carcinoma. mutations VHL, VAL166PHE number 13 clinvarAccessions RCV000002310;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030824 text In a family with VHL ({193300}), {67:Neumann et al. (1995)} identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma ({104:Zbar et al., 1996}). In 6 members of the same German family identified by {67:Neumann et al. (1995)} with von Hippel-Lindau syndrome type 2C, {98:Weirich et al. (2002)} found a P81S mutation in the VHL gene ({608537.0020}) which cosegregated with the L188V mutation. {98:Weirich et al. (2002)} discussed the possible impact of these mutations on protein function and phenotype. In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; {263400}), {74:Pastore et al. (2003)} identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation was in compound heterozygous state with the common R200W mutation ({608537.0019}). {65:Neumann et al. (2002)} identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma ({171300}). The mutation was not identified in 600 control chromosomes. mutations VHL, LEU188VAL number 14 alternativeNames ERYTHROCYTOSIS, FAMILIAL, 2, INCLUDED;; PHEOCHROMOCYTOMA, INCLUDED clinvarAccessions RCV000002311;;1;;;RCV000002313;;1;;;RCV000002312;;1 status live name PHEOCHROMOCYTOMA dbSnps rs104893826 text In an uncle and his nephew with apparently isolated pheochromocytoma ({171300}), {92:van der Harst et al. (1998)} found an arg64-to-pro (R64P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by {92:van der Harst et al. (1998)} that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also {608537.0016}). mutations VHL, ARG64PRO number 15 clinvarAccessions RCV000132356;;1;;;RCV000002314;;1 status live name PHEOCHROMOCYTOMA dbSnps rs104893827 text In a patient with apparently sporadic pheochromocytoma ({171300}), {92:van der Harst et al. (1998)} found a leu63-to-pro (L63P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by {92:van der Harst et al. (1998)} that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also {608537.0015}). mutations VHL, LEU63PRO number 16 clinvarAccessions RCV000002315;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs104893824 text In a family with VHL ({193300}), {8:Bradley et al. (1999)} identified a 547T-A transversion in exon 1 of the VHL gene, resulting in a tyr112-to-asn (Y112N) substitution. Of 13 affected individuals, 7 had renal cell carcinoma and 1 had pheochromocytoma. The authors contrasted this family to 2 families reported by {12:Chen et al. (1996)} that had a mutation at the same position but causing a different amino acid change (tyr112 to his; {608537.0012}). In these families, 19 of 22 affected individuals had pheochromocytoma and none had renal cell carcinoma. {8:Bradley et al. (1999)} concluded that different amino acid changes at the same position can cause very distinct clinical phenotypes. mutations VHL, TYR112ASN number 17 clinvarAccessions RCV000002316;;1 status live name RENAL CELL CARCINOMA WITH PARANEOPLASTIC ERYTHROCYTOSIS dbSnps rs28940297 text {99:Wiesener et al. (2002)} described a 50-year-old man, admitted to hospital for acute myocardial infarction, who was found to have marked erythrocytosis. Serum erythropoietin (EPO; {133170}) was increased, and ultrasonography demonstrated a mass at the upper pole of the left kidney. Following nephrectomy, which confirmed the diagnosis of renal cell carcinoma ({144700}), EPO serum concentration decreased within 7 days and hemoglobin levels returned to normal. The patient was well 9 months later with normal EPO serum concentration. In this patient, {99:Wiesener et al. (2002)} reported that EPO mRNA was not detectable in normal kidney tissue but markedly upregulated in the tumor. Hypoxia-inducible genes, including VEGF ({192240}), GLUT1 ({138140}), carbonic anhydrase-9 ({603179}), lactate dehydrogenase-A ({150000}), and aldolase A ({103850}), were also strongly induced in the tumor. Immunoblots showed significant overexpression of the HIF1A ({603348}) and HIF2A ({603349}) subunits in the tumor, and immunohistochemistry performed for HIF1A showed nuclear accumulation of the transcription factor in virtually every tumor cell. A mutation analysis of the VHL gene in tumor cells revealed a leu163-to-pro (L163P) missense mutation due to a 701T-C transition in exon 3. This mutation had previously been identified in another RCC. The mutation was not present in other tissues of the patient. In this case, there was a clear indication that the pronounced erythrocytosis was a precipitating factor in the coronary thrombosis. mutations VHL, LEU163PRO number 18 clinvarAccessions RCV000002319;;1 status live name POLYCYTHEMIA, CHUVASH TYPE dbSnps rs28940298 text Chuvash polycythemia, familial erythrocytosis-2 ({263400}) caused by this specific mutation, is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. {3:Ang et al. (2002)} studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin (EPO; {133170}) levels and ruled out a location of the gene on chromosome 11 as had been reported previously by {93:Vasserman et al. (1999)}. They also ruled out mutation in the HIF1A gene ({603348}), which is located in 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a 598C-T transition in the VHL gene, resulting in an arg200-to-trp (R200W) mutation in all cases. {4:Ang et al. (2002)} concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 ({138140}), transferrin (TF; {190000}), transferrin receptor (TFRC; {190010}), and vascular endothelial growth factor (VEGF; {192240}). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. {4:Ang et al. (2002)} stated that more than 700 mutations had been reported in VHL ({7:Beroud et al., 1998}), but that no individual had been found to be homozygous or compound heterozygous for germline mutations. {75:Pastore et al. (2003)} evaluated the role of the VHL gene in 8 children with a history of polycythemia and an elevated serum EPO level and identified 3 different germline VHL mutations in 4 of them. One child was homozygous for the R200W mutation, and another was compound heterozygous for the R200W mutation and a val130-to-leu mutation (V130L; {608537.0021}). Of 2 sibs who were heterozygous for an asp126-to-tyr mutation (D126Y; {608537.0022}), 1 fulfilled some criteria of VHL syndrome ({193300}); a pulmonary angioma was discovered at 10 years of age and treated by coil embolization without effect on the polycythemia, and at 15 years of age nephrectomy was performed for a subcapsular hemangioma. {78:Percy et al. (2002)} observed homozygosity for the R200W mutation in 3 Bangladeshi families with Chuvash-type congenital polycythemia living in the United Kingdom. By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation, including 72 Chuvash individuals, {55:Liu et al. (2004)} determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago. In a matched cohort study, {33:Gordeuk et al. (2004)} found that homozygosity for the 598C-T transition in the VHL gene was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF concentrations (p less than 0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of HIF1-alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in 598C-T homozygotes than in controls, erythropoietin response to hypoxia was identical. {33:Gordeuk et al. (2004)} concluded that Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. {10:Cario et al. (2005)} reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted. {79:Perrotta et al. (2006)} found that the R200W missense mutation (598C-T) causing Chuvash polycythemia is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single founder hypothesis. {79:Perrotta et al. (2006)} also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of {78,77:Percy et al. (2002, 2003)}. {84:Russell et al. (2011)} presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D ({608537.0024}) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 ({603348}). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; {133170}) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 ({603597}), which inhibits binding and degradation of phosphorylated JAK2 ({147796}). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 ({601511}) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice. mutations VHL, ARG200TRP number 19 clinvarAccessions RCV000122262;;0;;;RCV000002320;;2 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs104893829 text In 6 members of a German family in which the L188V mutation in the VHL gene ({608537.0014}) had previously been identified in association with von Hippel-Lindau syndrome type 2C ({193300}), {98:Weirich et al. (2002)} identified a 454C-T transition in exon 1 of the VHL gene, resulting in a pro81-to-ser (P81S) mutation. The concurrent P81S mutation was identified by novel screening approaches, including denaturing high-performance liquid chromatography (DHPLC) and sequencing. The 2 mutations cosegregated with the syndrome. {98:Weirich et al. (2002)} discussed the possible impact of the mutations on protein function and phenotype. mutations VHL, PRO81SER number 20 clinvarAccessions RCV000115744;;1;;;RCV000002321;;2 status live name ERYTHROCYTOSIS, FAMILIAL, 2 dbSnps rs104893830 text See {608537.0019} and {75:Pastore et al. (2003)}. mutations VHL, VAL130LEU number 21 clinvarAccessions RCV000002317;;1;;;RCV000030586;;1 status live name ERYTHROCYTOSIS, FAMILIAL, 2 dbSnps rs104893831 text See {608537.0019} and {75:Pastore et al. (2003)}. mutations VHL, ASP126TYR number 22 clinvarAccessions RCV000002318;;1 status live name ERYTHROCYTOSIS, FAMILIAL, 2 dbSnps rs28940300 text In a 10-year-old white American boy who presented at age 9 years with familial erythrocytosis ({263400}), {74:Pastore et al. (2003)} identified compound heterozygosity for a 574C-T transition in the VHL gene, resulting in a pro192-to-ser (P192S) change, and the common R200W mutation ({608537.0019}). mutations VHL, PRO192SER number 23 clinvarAccessions RCV000002322;;1 status live name ERYTHROCYTOSIS, FAMILIAL, 2 dbSnps rs28940301 text In a 17-year-old Croatian boy who presented at age 1 year with familial erythrocytosis ({263400}), {74:Pastore et al. (2003)} identified homozygosity for a 571C-G transversion in the VHL gene, resulting in a his191-to-asp (H191D) change. {84:Russell et al. (2011)} presented evidence suggesting 2 main molecular mechanisms by which the H191D and R200W ({608537.0019}) VHL mutations result in polycythemia. In vitro studies showed that the H191D mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 ({603348}). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; {133170}) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 ({603597}), which inhibits binding and degradation of phosphorylated JAK2 ({147796}). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 ({601511}) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice. mutations VHL, HIS191ASP number 24 clinvarAccessions RCV000002323;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs5030827 text Following the revised codon numbering system of {51:Kuzmin et al. (1995)}, the VAL155LEU (V155L) mutation has been renumbered as V84L. In 2 sibs from Wales with bilateral pheochromocytoma without other features of VHL syndrome, consistent with VHL type 2C ({193300}), {16:Crossey et al. (1995)} identified a heterozygous 463G-T transversion in exon 1 of the VHL gene, resulting in a val155-to-leu (V155L) substitution. {1:Abbott et al. (2006)} identified the V84L substitution in affected individuals from 3 unrelated families with early-onset isolated pheochromocytoma consistent with VHL syndrome type 2C. Although no other signs of VHL syndrome were present in 7 patients, 1 patient was suspected to have a spinal hemangioblastoma based on imaging studies. mutations VHL, VAL84LEU number 25 clinvarAccessions RCV000002324;;1;;;RCV000036541;;1 status live name PHEOCHROMOCYTOMA dbSnps rs5030808 text In the germlines of 2 unrelated patients with sporadic pheochromocytoma ({171300}), {65:Neumann et al. (2002)} identified a 490G-A transition in exon 1 of the VHL gene, resulting in a gly93-to-ser (G93S) substitution. The mutation was not identified in 600 control chromosomes. mutations VHL, GLY93SER number 26 clinvarAccessions RCV000002325;;1 status live name VON HIPPEL-LINDAU SYNDROME dbSnps rs267607170 text In a 2.5-year-old girl who presented with a pheochromocytoma but no other manifestations of von Hippel-Lindau syndrome ({193300}), {87:Sovinz et al. (2010)} identified a heterozygous 491A-G transition in exon 3 of the VHL gene, resulting in an gln164-to-arg (Q164R) substitution in a protein surface residue. Genotyping of the family indicated that she inherited the mutation from her father, in whom it occurred de novo. Although he was in good health and asymptomatic, detailed physical examination found a retinal angioma, an adrenal adenoma, and bilateral pheochromocytoma, consistent with VHL syndrome. {87:Sovinz et al. (2010)} noted that {73:Ong et al. (2007)} had identified the Q164R mutation in a family in which a patient developed pheochromocytoma at age 10 years and retinal angioma at age 23 years, suggesting that this mutation may be associated with early onset of symptoms. mutations VHL, GLN164ARG number 27 clinvarAccessions RCV000002326;;1 prefix * titles preferredTitle VHL GENE; VHL textSectionList textSection textSectionTitle Description textSectionContent The evolutionarily conserved VHL gene encodes 2 protein products, a 30-kD full-length form (p30) and a 19-kD form (p19). The protein products of the VHL gene play a role in the oxygen-sensing pathway, in microtubule stability and orientation, tumor suppression, cilia formation, regulation of senescence, cytokine signaling, collagen IV (see {120130}) regulation, and assembly of a normal extracellular fibronectin matrix (summary by {69:Nordstrom-O'Brien et al., 2010}). textSectionName description textSectionTitle Cloning textSectionContent By positional cloning, {52:Latif et al. (1993)} identified the VHL tumor suppressor gene. The gene encodes a 213-amino acid protein with a predicted acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. The authors identified 2 widely expressed mRNA transcripts of approximately 6 and 6.5 kb. {41:Iliopoulos et al. (1995)} demonstrated that the product of the VHL gene is an approximately 30-kD protein. By screening a rat liver cDNA library, {20:Duan et al. (1995)} isolated the rat VHL gene, which is predicted to encode a 185-amino acid protein. The rat protein is 88% identical to the aligned 213-amino acid human VHL gene product. The human and rat proteins had molecular masses of 28 and 21 kD, respectively. {81:Richards et al. (1996)} used in situ hybridization to investigate the principal sites of VHL expression during embryogenesis. They also analyzed a variety of fetal tissues for levels of the 2 VHL isoforms, isoform I, which contains all 3 exons, and isoform II, which contains only exons 1 and 3. Although VHL expression was found to be ubiquitous, particularly high levels of expression were detected in the urogenital system, brain, spinal cord, sensory ganglia, eyes, and bronchial epithelium. {81:Richards et al. (1996)} noted that this expression pattern correlated to some extent with the pattern of organ involvement in VHL syndrome but that there were significant differences. Both isoforms of VHL were detected in all tissues, and the ratio of isoforms was similar between tissues. {86:Schoenfeld et al. (1998)} identified a second native VHL gene product. They showed that this 18-kD protein is initiated from the second translation start site at codon 54, which contains a more conserved Kozak consensus sequence and thus may serve as a second, internal, translation initiation site. The significance of a second translation start site is underscored by the lack of mutations found between the first and second methionine codons of the VHL gene in both sporadic and VHL-associated renal carcinomas. This observation suggested that mutation in this region may not lead to VHL inactivation if translation could be initiated at the second methionine codon, producing a functional VHL protein. Furthermore, both the rat and mouse contain only 19 of the 53 amino acids present in this region in the human VHL ORF. {86:Schoenfeld et al. (1998)} concluded that the 18-kD protein contains the biologic activity of the VHL gene. {43:Iliopoulos et al. (1998)} also demonstrated that in addition to the 213-amino acid VHL protein with an apparent molecular mass of 30 kD (VHL30), a second VHL protein (VHL19) resulted from internal translation from the second methionine within the VHL ORF. VHL30 resides primarily in the cytosol, with lower amounts found in the nucleus or associated with cell membranes. In contrast, VHL19 is equally distributed between the nucleus and cytosol and is not found in association with membranes. VHL19, like VHL30, can bind to elongin B ({600787}), elongin C ({600788}), and Hs-Cul2 in coimmunoprecipitation assays and can inhibit the production of hypoxia-inducing proteins such as VEGF ({192240}) and GLUT1 ({138140}) when reintroduced into renal carcinoma cells that lack a wildtype VHL allele. Thus, cells contain 2 biologically active VHL gene products. textSectionName cloning textSectionTitle Gene Structure textSectionContent {52:Latif et al. (1993)} determined that the VHL gene contains at least 3 exons. {103:Zatyka et al. (2002)} analyzed the promoter region of the VHL gene and found 4 regions of conservation between human, primate, and rodent sequences. In silico analysis identified binding sites for numerous transcription factors within the conserved regions, and deletion analysis of the promoter in a reporter assay in 293 and HeLa cells identified 1 negative and 2 positive regulatory elements. The promoter contains a functional SP1 ({189906}) site and overlapping SP1/AP2 ({107580}) sites. textSectionName geneStructure textSectionTitle Gene Function textSectionContent Role in Tumor Suppression {58:Maher et al. (1990)} compared age incidence curves for sporadic cerebellar hemangioblastoma and sporadic renal cell carcinoma to those for familial forms of these tumors that occur as part of von Hippel-Lindau syndrome ({193300}). The curves for tumors in VHL syndrome were compatible with a single mutation model, whereas the age incidence curves for sporadic tumors suggested a 2-stage mutation process. On the whole, the findings suggested that the VHL gene functions as a recessive tumor suppressor gene. {17:Crossey et al. (1994)} presented convincing evidence that the VHL syndrome gene functions as a recessive tumor suppressor gene and that inactivation of both alleles of the VHL gene is a critical event in the pathogenesis of VHL neoplasms. Studies of loss of heterozygosity (LOH) showed that in 7 tumors from 7 familial cases in which the parental origin of the 3p26-p25 allele loss could be determined, the allele had been lost from the chromosome inherited from the unaffected parent. In 4 VHL tumors, LOH on other chromosomes (5q21, 13q, 17q) was found, indicating that homozygous VHL gene mutations may be required but not sufficient for tumorigenesis in von Hippel-Lindau syndrome. When expressed in COS-7 cells, {20:Duan et al. (1995)} found that both the human and the rat VHL proteins showed predominant nuclear, nuclear and cytosolic, or predominant cytosolic VHL staining by immunofluorescence. A complicated pattern of cellular proteins was seen that could be specifically coimmunoprecipitated with the introduced VHL protein. A complex containing VHL and proteins with apparent molecular masses of 16 and 9 kD was the most consistently observed. Certain naturally occurring VHL missense mutations demonstrated either complete or partial loss of the p16-p9 complex. {20:Duan et al. (1995)} concluded that the VHL tumor suppressor gene product is a nuclear protein, perhaps capable of specifically translocating between the nucleus and the cytosol. They suggested that VHL may execute its function via formation of specific multiprotein complexes. {94:Vogelstein (1995)} referred to the VHL gene as a gatekeeper gene for cancers such as those of the kidney. {83:Rubenstein and Yaari (1994)} suggested that the VHL gene may serve that role in relation to astrocytoma. They presented the pedigree of a Puerto Rican family in which at least 9 members had von Hippel-Lindau syndrome and 2 of these had astrocytoma. To elucidate the biochemical mechanisms underlying tumor suppression by the VHL protein, {21:Duan et al. (1995)} and {50:Kibel et al. (1995)} searched for cellular proteins that bind to wildtype VHL protein but not to tumor-derived VHL protein mutants. They found that 2 transcriptional elongation factors, elongin B ({600787}) and elongin C ({600788}), bind in vitro and in vivo to a short, colinear region of the VHL protein that is frequently mutated in human tumors. {50:Kibel et al. (1995)} showed that a peptide replica of this region inhibited binding of VHL protein to elongin B and elongin C, whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. {21:Duan et al. (1995)} showed that recombinant VHL competes with elongin A ({600786}) for elongin B and C binding in vitro. The results were interpreted as indicating that the normal tumor suppression function of VHL protein involves the inhibition of transcription elongation by its binding to elongin B and elongin C. In a review article, {91:Tyers and Willems (1999)} stated that the VHL protein is part of a complex that includes elongin B, elongin C, and cullin-2 (CUL2; {603135}), proteins that are associated with transcriptional elongation and ubiquitination. Components of the VCB (VHL/elongin C/elongin B) complex share sequence similarities with the E3 ubiquitin ligase complexes SCF (SKP1, ({601434}); CUL1, ({603134}); F-box protein) and APC (anaphase promoting complex; see {603462}). Thus, elongin B is ubiquitin-like, and elongin C and CUL2 are similar to the SKP1 and CUL1 components of SCF, respectively. Substrate recognition by E3 enzymes such as SCF and APC is crucial because protein degradation must be highly selective. Both SCF and APC interact with a set of adaptor proteins that recruit different binding partners through specific protein-protein interaction domains. SOCS-box-containing proteins (see {603597}) may act as adaptors for the VCB complex. {25:Feldman et al. (1999)} demonstrated that the folding and assembly of VHL into a complex with its partner proteins, elongin B and elongin C, is directly mediated by the chaperonin TRiC, also called CCT (see {600114}). Association of VHL with TRiC is required for formation of the VHL-elongin B-elongin C complex. A 55-amino acid domain of VHL (amino acids 100 to 155) is both necessary and sufficient for binding to TRiC. Mutation or deletion of this domain is associated with VHL syndrome, and 2 mutations that disrupt the normal interaction with TRiC and impair VHL folding were identified. These results defined a novel role for TRiC in mediating oligomerization and suggested that inactivating mutations can impair polypeptide function by interfering with chaperone-mediated folding. {54:Lee et al. (1996)} demonstrated that there is a tightly regulated, cell-density-dependent transport of the VHL protein into and/or out of the nucleus. In densely grown cells, it is predominantly in the cytoplasm, whereas in sparse cultures, most of the protein can be detected in the nucleus. They identified a putative nuclear localization signal in the first 60 and first 28 amino acids of the human and rat VHL protein, respectively. Sequences in the C-terminal region of VHL protein may also be required for localization to the cytosol. The findings indicated a novel cell-density-dependent pathway responsible for the regulation of VHL cellular localization. {41:Iliopoulos et al. (1995)} showed that the renal cell carcinoma cell line 786-O, which is known to harbor a VHL mutation, fails to produce a wildtype VHL protein. Reintroduction of wildtype, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumors in nude mice. Like many cancer cells, the 786-0 RCC fails to exit the cell cycle upon serum withdrawal. {76:Pause et al. (1998)} showed that reintroduction of the wildtype VHL gene restores the ability of VHL-negative RCC cells to exit the cell cycle and enter G0/quiescence in low serum. The cyclin-dependent kinase inhibitor p27 (CDKN1B; {600778}) accumulates upon serum withdrawal, only in the presence of VHL, as a result of an increase in protein stability. {76:Pause et al. (1998)} proposed that loss of the wildtype VHL gene results in a specific cellular defect in serum-dependent growth control, which may initiate tumor formation. Thus, VHL appears to be the first tumor suppressor involved in the regulation of cell cycle exit, which is consistent with its gatekeeper function in the kidney. To discover genes involved in VHL-mediated carcinogenesis, {45:Ivanov et al. (1998)} used renal cell carcinoma cell lines stably transfected with wildtype VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12 ({603263}). The deduced protein sequence was classified as a one-pass transmembrane carbonic anhydrase possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wildtype VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9 ({603179}) which encodes another transmembrane carbonic anhydrase with an intact catalytic domain. Although both domains of the VHL protein contributed to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. By fluorescence in situ hybridization, {45:Ivanov et al. (1998)} mapped CA12 and CA9 to chromosome bands 15q22 and 17q21.2, respectively, regions prone to amplification in some human cancers. {45:Ivanov et al. (1998)} stated that additional experiments were necessary to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth. {82:Roe et al. (2006)} found that VHL directly associated with and stabilized p53 (TP53; {191170}) by suppressing MDM2 ({164785})-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, VHL invoked an interaction between p53 and p300 (EP300; {602700}) and the acetylation of p53, which led to an increase in p53 transcriptional activity and cell cycle arrest and apoptosis. {82:Roe et al. (2006)} concluded that VHL has a function in upregulating p53. {100:Yang et al. (2007)} noted that VHL-defective renal carcinoma cells exhibit increased NF-kappa-B (see {164011}) activity, which can promote resistance to chemotherapy or cytokines. They showed that VHL downregulates NF-kappa-B activity by acting as an adaptor to promote casein kinase-2 (see {115440})-mediated inhibitory phosphorylation of CARD9 ({607212}), an NF-kappa-B agonist. Role in Oxygen-Related Gene Expression The highly vascular tumors associated with von Hippel-Lindau syndrome overproduce angiogenic peptides such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF; {192240}). {42:Iliopoulos et al. (1996)} found that renal carcinoma cells lacking wildtype VHL protein produce mRNAs encoding VEGF/VPF, the glucose transporter GLUT1 (SLC2A1; {138140}), and the platelet-derived growth factor B chain ({190040}) under both normoxic and hypoxic conditions. Reintroduction of wildtype, but not mutant, VHL protein into these cells specifically inhibited production of these mRNAs under normoxic conditions, thus restoring their previously described hypoxia-inducible profile. {42:Iliopoulos et al. (1996)} concluded that the VHL protein appears to play a critical role in the transduction of signals generated by changes in ambient oxygen tension. VEGF mRNA is upregulated in von Hippel-Lindau syndrome-associated tumors. {64:Mukhopadhyay et al. (1997)} assessed the effect of the VHL gene product on VEGF expression. Using a VEGF promoter-luciferase construct for cotransfection with a wildtype VHL vector in embryonic kidney and renal cell carcinoma cell lines, they showed that wildtype VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically bound the transcription factor Sp1 ({189906}) in crude nuclear extracts. They further demonstrated that VHL and Sp1 directly interact with an inhibitory effect on Sp1, suggesting that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau syndrome and renal cell carcinoma. {61:Maxwell et al. (1999)} studied the involvement of VHL in oxygen-regulated gene expression using ribonuclease protection analysis of 2 VHL-deficient renal carcinoma cell lines, RCC4 and 786-O. Eleven genes encoding products involved in glucose transport, glycolysis, high energy phosphate metabolism, and angiogenesis were examined; 9 were induced by hypoxia in other mammalian cells and 2 were repressed by hypoxia. None of these responses were seen in the VHL-defective cell lines. Responses to hypoxia were restored by stable transfection of a wildtype VHL gene, with effects ranging from a modest action of hypoxia to substantial regulation. These results indicated that the previously described upregulation of hypoxia-inducible mRNAs in VHL-defective cells extend to a broad range of oxygen-regulated genes and involves a constitutive 'hypoxia pattern' for both positively and negatively regulated genes. Hypoxia-inducible factor-1 (HIF1; {603348}) has a key role in cellular response to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis, and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. {61:Maxwell et al. (1999)} demonstrated a critical role for the von Hippel-Lindau tumor suppressor gene product VHL in HIF1 regulation. In VHL-defective cells, HIF-alpha subunits were constitutively stabilized and HIF1 was activated. Reexpression of VHL restored oxygen-dependent instability. VHL and HIF-alpha subunits coimmunoprecipitated, and VHL was present in the hypoxic HIF1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF1 is dissociated from VHL. These findings indicated that the interaction between HIF1 and VHL is iron dependent and that it is necessary for the oxygen-dependent degradation of HIF-alpha subunits. {61:Maxwell et al. (1999)} suggested that constitutive HIF1 activation may underlie the angiogenic phenotype of VHL-associated tumors. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the VHL tumor suppressor protein. {44:Ivan et al. (2001)} found that human VHL protein binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and iron, this protein modification may play a key role in mammalian oxygen sensing. {46:Jaakkola et al. (2001)} also demonstrated that the interaction between VHL protein and a specific domain of the HIF1-alpha subunit is regulated through hydroxylation of a proline residue (HIF1-alpha P564) by an enzyme which they termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as a cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor. {59:Mahon et al. (2001)} showed that the N-terminal 155 residues of VHL interact with HIF1AN ({606615}). They found that VHL functions as a transcriptional corepressor inhibiting HIF1A transactivation by recruiting HDAC1 ({601241}), HDAC2 ({605164}), and HDAC3 ({605166}). {23:Epstein et al. (2001)} defined a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and identified Egl9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, they showed that the HIF-prolyl hydroxylases are represented by 3 proteins, PHD1 ({606424}), PHD2 ({606425}), and PHD3 ({606426}), with a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrored the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF. {39:Hoffman et al. (2001)} reported that the products of 4 different type 2C VHL alleles retain the ability to downregulate HIF but are defective for promotion of fibronectin ({135600}) matrix assembly. Furthermore, leu188 to val (L188V; {608537.0014}), a well-studied type 2C mutation, retained the ability to suppress renal carcinoma growth in vivo. {13:Clifford et al. (2001)} investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wildtype binding patterns with VHL interacting proteins, suggesting that loss of other VHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A, and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of fibronectin binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of fibronectin binding. These studies strengthened the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raised the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL syndrome. Hemangioblastomas of the central nervous system and retina in VHL patients overexpress vascular endothelial growth factor, which represents a potential target for anti-angiogenic drugs. In 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416, {80:Richard et al. (2002)} observed, after 3 to 4 months of treatment, a secondary paradoxical polycythemia. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia had never been reported in SU5416 trials for advanced malignancies. In the studies of {80:Richard et al. (2002)}, the polycythemia may have represented a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene. {88:Staller et al. (2003)} demonstrated that the VHL tumor suppressor protein negatively regulates CXCR4 ({162643}) expression owing to its capacity to target HIF1A ({603348}) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. {88:Staller et al. (2003)} concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs. {15:Corn et al. (2003)} established that the VHL protein binds to Tat-binding protein-1 (TBP1; {186852}). TBP1 associates with the beta-domain of VHL and complexes with VHL and HIF1A in vivo. Overexpression of TBP1 promotes degradation of HIF1A in a VHL-dependent manner that requires the ATPase domain of TBP1. Several distinct mutations in exon 2 of the VHL gene disrupt binding of VHL to TBP1. A VHL protein mutant containing an exon 2 missense substitution coimmunoprecipitated with HIF1A, but not TBP1, and did not promote degradation of HIF1A. Thus, the ability of the VHL protein to degrade HIF1A depends in part on its interaction with TBP1 and suggests a new mechanism for HIF1A stabilization in some VHL-deficient tumors. To identify novel target genes of the VHL protein, {102:Zatyka et al. (2002)} investigated the effect of wildtype VHL protein on the expression of 588 cancer-related genes in 2 VHL-defective renal cell carcinoma cell lines. Expression array analysis identified 9 genes that demonstrated a greater than 2-fold decrease in expression in both RCC cell lines after restoration of wildtype VHL protein. Three of the 9 genes, VEGF, PAI1 ({173360}), and LRP1 ({107770}), had previously been reported as targets of the VHL protein and are hypoxia-inducible. In addition, 6 novel targets were detected, including cyclin D1 (CCND1; {168461}). No evidence was found that CCND1 expression was influenced by hypoxia, suggesting that VHL protein downregulates these targets by an HIF-independent mechanism. Homozygous disruption of the Vhl gene in mice results in embryonic lethality from lack of placental vasculogenesis ({32:Gnarra et al., 1997}). To investigate Vhl function in the adult, {35:Haase et al. (2001)} generated a conditional Vhl-null allele (2-lox allele) and a null allele (1-lox allele) by Cre-mediated recombination in embryonic stem cells. They showed that mice heterozygous for the 1-lox allele developed cavernous hemangiomas of the liver, a rare manifestation in the human disease. Histologically, these tumors were associated with hepatocellular steatosis and focal proliferations of small vessels. To study the cellular origin of these lesions, {35:Haase et al. (2001)} inactivated VHL tissue specifically in hepatocytes. Deletion of VHL in the liver resulted in severe steatosis, many blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma. These histopathologic changes were similar to those seen in livers from mice heterozygous for the 1-lox allele. Hypoxia-inducible mRNAs encoding vascular endothelial growth factor, glucose transporter-1, and erythropoietin (EPO; {133170}) were upregulated. Thus, targeted inactivation of mouse Vhl replicated clinical features of the human disease and underscored the importance of the VHL gene product in the regulation of hypoxia-responsive genes in vivo. {97:Wang et al. (2007)} showed that mice overexpressing Hif1a in osteoblasts through selective deletion of Vhl expressed high levels of Vegf ({192240}) and developed extremely dense, heavily vascularized long bones. In contrast, mice lacking Hif1a in osteoblasts had long bones that were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. {97:Wang et al. (2007)} concluded that activation of the HIF1A pathway in osteoblasts during bone development couples angiogenesis to osteogenesis. Endocytosis plays a major role in the deactivation of receptors localized to the plasma membrane, and early endocytic events require the small GTPase RAB5 ({179512}) and its effector rabaptin-5 (RABEP1; {603616}). {96:Wang et al. (2009)} found that hypoxia, via the VHL-HIF2A ({603349}) signaling pathway, downregulated rabaptin-5 expression, leading to decelerated endocytosis and prolonged activation of ligand-bound EGFR ({131550}). Primary kidney and breast tumors with strong hypoxic signatures showed significantly lower expression of rabaptin-5 RNA and protein. {96:Wang et al. (2009)} identified a conserved hypoxia-responsive element (HRE) in the rabaptin-5 promoter that bound in vitro-translated HIF1A and HIF2A, leading to displacement of RNA polymerase II and attenuating rabaptin-5 transcription. {62:Mehta et al. (2009)} reported that in C. elegans the loss of VHL1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF1 ({603348}) was epistatic to VHL1, indicating that HIF1 acts downstream of VHL1 to modulate aging and proteotoxicity. VHL1 and HIF1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. {62:Mehta et al. (2009)} concluded that their findings define VHL1 and the hypoxic response as an alternative longevity and protein homeostasis pathway. {84:Russell et al. (2011)} demonstrated that VHL binds to SOCS1 ({603597}) and promotes degradation of phosphorylated JAK2 ({147796}) via ubiquitin-mediated destruction. Role in Protein Assembly {71:Ohh et al. (1998)} showed that fibronectin coimmunoprecipitated with normal VHL protein but not tumor-derived VHL mutants. Immunofluorescence and biochemical fractionation experiments showed that fibronectin colocalized with a fraction of VHL associated with the endoplasmic reticulum, and cold competition experiments suggested that complexes between fibronectin and VHL protein exist in intact cells. Assembly of an extracellular fibronectin matrix by VHL -/- renal carcinoma cells, as determined by immunofluorescence and ELISA assays, was grossly defective compared with VHL +/+ renal carcinoma cells. Reintroduction of wildtype, but not mutant, VHL protein into VHL -/- renal carcinoma cells partially corrected this defect. Extracellular fibronectin matrix assembly by VHL -/- mouse embryos and mouse embryo fibroblasts, unlike their VHL +/+ counterparts, was grossly impaired. {71:Ohh et al. (1998)} concluded that VHL protein is important in fibronectin matrix assembly. {36:Hergovich et al. (2003)} found that VHL is a microtubule-associated protein that can protect microtubules from depolymerization in several cell lines. Both the microtubule binding and stabilization functions depended on amino acids 95-123, a hotspot for mutations in VHL syndrome. They found that the syndrome-associated mutations Y98H ({608537.0009}) and Y112H ({608537.0012}) disrupted the microtubule-stabilizing function of the protein. Role in Ciliary Maintenance Using immunofluorescence and confocal microscopy, {57:Lolkema et al. (2008)} showed that Vhl localized to cilia extending from basal bodies stained with gamma-tubulin (TUBG1; {191135}) in primary mouse kidney cells. Cilia were absent in renal cell carcinoma cells derived from a VHL patient, but reintroduction of VHL into these cells resulted in rapid cilia assembly. The cilia function of VHL required residues 1 to 53, which constitute an acidic domain, and residues 95 to 123, which were previously implicated in microtubule binding and tumor suppression. Role in Central Nervous System Development {48:Kanno et al. (2000)} investigated the role of the VHL gene in CNS development using rodent CNS progenitor cells. They showed that expression of the VHL protein is correlated with neuronal differentiation but not with glial differentiation in CNS progenitor cells, and also that VHL gene transduction induces neuronal differentiation. Furthermore, a VHL mRNA antisense oligonucleotide inhibited differentiation of CNS progenitor cells and upregulated their cell cycle. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent Crystal Structure The ubiquitination of HIF by VHL plays a central role in the cellular response to changes in oxygen availability. VHL protein binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. {63:Min et al. (2002)} determined the 1.85-angstrom structure of a 20-residue HIF1A-VHL protein-elongin B-elongin C complex that shows that HIF1A binds to VHL protein in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the VHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling. {40:Hon et al. (2002)} determined the crystal structure of a hydroxylated HIF1A peptide bound to the VHL protein, elongin C, and elongin B and performed solution binding assays, which revealed a single, conserved hydroxyproline-binding pocket in the VHL protein. They found that optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. {40:Hon et al. (2002)} concluded that this mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent {69:Nordstrom-O'Brien et al. (2010)} provided a review of the molecular genetics of the VHL gene, including the mutational spectrum and associated phenotypes. Von Hippel-Lindau Syndrome Using restriction fragment analysis, {52:Latif et al. (1993)} identified rearrangements of the VHL gene in 28 of 221 kindreds with von Hippel-Lindau syndrome ({193300}). Eighteen of these rearrangements were due to deletion in the candidate gene. Using pulsed field gel electrophoresis and cosmid mapping, {52:Latif et al. (1993)} established a physical map of the VHL gene region and identified 3 large nonoverlapping constitutional deletions in 3 unrelated VHL patients; 1 of these was an in-frame 3-nucleotide deletion at nucleotide 434, predicted to remove ile146 in the gene product ({608537.0001}). Using single-strand conformation polymorphism and heteroduplex analysis to investigate 94 VHL patients without large deletions, {18:Crossey et al. (1994)} identified 40 different mutations in the VHL gene in 55 unrelated kindreds: 19 missense mutations, 6 nonsense mutations, 12 frameshift deletions or insertions, 2 in-frame deletions, and 1 splice donor site mutation. The 2 most frequent mutations were arg238-to-gln ({608537.0005}) and arg238-to-trp ({608537.0003}), which were detected in 5 and 4 unrelated kindreds, respectively. {72:Olschwang et al. (1998)} screened 92 unrelated patients with VHL syndrome for point mutations and found 61 DNA variants. In addition, a search for EcoRI rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided into 20 mutations predicted to alter the open reading frame and 43 DNA sequence variants that on a priori grounds were of unknown biologic consequence. The 3-prime end of the coding sequence of the VHL gene, which encodes the elongin (see {600787})-binding domain, was the site of 5 of 20 truncating mutations (25%) and 18 of 41 DNA variants (44%) of uncertain functional significance. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants. {95:Wait et al. (2004)} performed genetic analysis of 5 CNS hemangioblastomas excised from 3 related VHL patients with the same germline VHL gene deletion. All of the tumors showed distinct 'second-hit' point mutations on the wildtype allele, even those tumors originating in the same patient. Moreover, the same types of tumors from the same locations also showed different point mutations. {95:Wait et al. (2004)} concluded that the somatic mutations were random, and that there is a unique mechanism underlying tumorigenesis in patients with germline deletion mutations. Using markers specific for chromosome 3, {31:Glasker et al. (2006)} mapped the deletion size of the 'second-hit' in 16 tumor tissue specimens from a single patient with VHL syndrome who had a germline heterozygous partial deletion in the VHL gene. The tumors consisted of 3 central nervous system hemangioblastomas, 7 renal cell carcinomas, 3 cystic renal structures, 2 pancreatic tumors, and 1 pancreatic cyst. Deletion size was highly variable, ranging from short deletions around the VHL gene to complete deletion of chromosome 3. However, there was no correlation between deletion size and site of the germline mutation, affected organ, or type or biological behavior of the tumor. {31:Glasker et al. (2006)} concluded that loss of VHL gene function alone is not immediately causative for neoplastic growth and suggested that further molecular events may be required for tumor formation. (For genotype/phenotype correlations in VHL syndrome, see {193300}.) Cancer The Knudson model predicts that sporadic cancers should be associated with mutations in the same locus affected in the corresponding hereditary cancer. Using SSCP and RT-PCR techniques, {52:Latif et al. (1993)} identified aberrant patterns in the VHL gene in 5 renal cell carcinoma (RCC) lines. In 4 of them, the pattern was due to small, 1- to 10-nucleotide deletions that created frameshift mutations and, presumably, truncated proteins. In the fifth RCC line, the change was a nonsense mutation, resulting from a 761C-A transversion. {22:Eng et al. (1995)} identified mutations in the VHL gene in 4 of 48 sporadic pheochromocytomas ({171300}). Two mutations were somatic and 2 were germline. In a mother and 2 sons with pheochromocytoma, {16:Crossey et al. (1995)} identified a VHL mutation (R238W; {6085327.0003}) mutation. None of them had evidence of VHL syndrome. In 30 (11%) of 271 unrelated patients with sporadic pheochromocytoma, {65:Neumann et al. (2002)} identified 22 different germline mutations in the VHL gene (see, e.g., {608537.0014} and {608537.0026}). {106:Zhuang et al. (1996)} analyzed VHL gene alterations in sporadic human colon carcinomas and adenomas using techniques that allowed for procurement and analysis of selected subpopulations of cells from paraffin embedded and frozen human tumor specimens. Allelic loss of the VHL gene was detected in 7 of 11 (64%) of informative patients with sporadic colon carcinoma. No allelic loss was shown in colon adenomas from 8 informative patients. The authors suggested that VHL gene loss may represent a relatively late event in colonic neoplasia progression. {70:Oberstrass et al. (1996)} found abnormalities of the VHL gene in 10 of 20 capillary hemangioblastomas of the CNS. Seven tumors had a frameshift mutation due either to deletion of 1 or more basepairs (6 cases) or to insertion of 1 basepair (1 case). The remaining 3 tumors had either point mutations with intron splice site sequences (2 cases) or a point mutation resulting in an amino acid substitution (1 case). Evidence for germline alterations of the VHL gene was found in 2 patients who showed identical mutations in both tumors and corresponding leukocyte DNA. {70:Oberstrass et al. (1996)} noted that it is significant that one of the 2 tumors with a germline mutation was in an 18-year-old male, and the other in a 40-year-old female. The non-germline mutations included tumors from individuals 70, 62, 60, 55, and 52 years old. {49:Kenck et al. (1996)} investigated 91 different parenchymal tumors of the kidney for mutation in the VHL gene by SSCP and/or heteroduplex techniques. Evidence of mutation of the VHL gene was associated exclusively with nonpapillary renal cell carcinoma. {24:Fearon (1997)} reviewed more than 20 different hereditary cancer syndromes that had been defined and attributed to specific germline mutations in various inherited cancer genes. In a useful diagram, he illustrated the roles of allelic variation ('1 gene - different syndromes') and genetic heterogeneity ('different genes - 1 syndrome') in inherited cancer syndromes. VHL mutations were used as an example of the former: inactivating mutations, such as nonsense mutations or deletions, predisposed to clear-cell renal carcinoma, retinal angioma, and cerebellar and spinal hemangioblastoma; missense mutations, e.g., in codon 167, predisposed to these tumors and pheochromocytoma in addition. {92:Van der Harst et al. (1998)} screened the VHL gene for germline mutations in 68 patients who were operated on for pheochromocytoma. This was undertaken to follow up on the work of {66:Neumann et al. (1993)}, who reported that, according to clinical criteria, approximately 23% of the apparently sporadic pheochromocytomas may in fact be related to a familial disorder; these disorders are, in addition to von Hippel-Lindau syndrome, neurofibromatosis-1 (NF1; {162200}) and multiple endocrine neoplasia types IIA (MEN2A; {171400}) and IIB (MEN2B; {162300}). They found mutations in the VHL gene in 8 patients; 2 patients were an uncle and nephew who had the same missense mutation, R64P ({608537.0015}). In 4 other patients, missense mutations, P25L, L63P ({608537.0016}), G144Q, and I147T, were identified. Three of these mutations (P25L, L63P, and R64P) were located closer to the N terminus of the VHL protein than any previously reported VHL mutation. In 2 other cases, the mutations were located not in the coding region but in the intronic sequence (but not within splice sites), adjacent to the exon, so that they were probably not related to the syndrome. The results suggested that 8.8% of patients (6 of 68) with apparently sporadic pheochromocytomas may carry germline mutations in the VHL gene. This is a relatively high proportion, although not as high as the 23% reported earlier. {27:Gallou et al. (1999)} investigated the nature of somatic VHL mutations in 173 primary sporadic human renal cell carcinomas using PCR and SSCP analysis. They detected an abnormal SSCP pattern in 73 samples. After sequencing, they identified microdeletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8%, and missense mutations in 17%. VHL mutations were found only in the nonpapillary renal cell carcinoma subtype, as previously reported. To compare somatic and germline mutations, they used the VHL database, which included 507 mutations. The study of mutational events revealed a significant difference between somatic and germline mutations. Mutations leading to truncated proteins were observed in 78% of somatic mutations but in only 37% of germline mutations (P less than 0.001). The authors postulated that a specific pattern of VHL mutations is associated with sporadic RCC. This pattern corresponds to mutations leading to truncated proteins, with few specific missense mutations. {6:Bender et al. (2000)} studied 36 VHL-related pheochromocytomas for somatic VHL and RET gene alterations and LOH of markers on chromosome arms 1p, 3p, and 22q. For comparison, they performed the same analyses in 17 sporadic pheochromocytomas. They found significantly different LOH frequencies at 3 loci between sporadic and VHL tumors; the more than 91% LOH of markers on 3p and the relatively low frequencies of LOH at 1p and 22q (15% and 21%, respectively) in VHL pheochromocytomas argue for the importance of VHL gene dysregulation and dysfunction in the pathogenesis of almost all VHL pheochromocytomas. In contrast, the relatively low frequency of 3p LOH (24%) and the lack of intragenic VHL alterations compared with the high frequency of 1p LOH (71%) and the moderate frequency of 22q LOH (53%) in sporadic pheochromocytomas argue for genes other than VHL, especially on 1p, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic versus VHL pheochromocytoma genesis are distinct. Renal cell carcinomas occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). In patients receiving dialysis, {101:Yoshida et al. (2002)} examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) for somatic mutations of the VHL gene as well as of the tyrosine kinase domain of the MET oncogene ({164860}) to address the molecular pathogenesis of ESRD/ACDK-associated RCCs. They found that 3 tumors had VHL frameshifts; 1 showed additional LOH at the VHL gene locus. All 3 tumors were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis, respectively. No mutations were found in the tyrosine kinase domain of the MET oncogene, where mutations had previously been found in cases of papillary RCCs. {60:Maranchie et al. (2004)} observed a paradoxically lower prevalence of RCC in patients with complete germline deletion of VHL. They retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p = 0.22), pancreas (p = 0.72), or pheochromocytoma (p = 0.34). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; {611183}), located within the 30-kb region of 3p, immediately telomeric to VHL (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. {26:Gallou et al. (2004)} studied the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were identified. The incidence of renal involvement was increased in families with mutations leading to protein truncation or large rearrangement, as compared to families with missense mutations (81% vs 63%, respectively; p = 0.03). In the group with missense mutations, {26:Gallou et al. (2004)} identified 2 mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCCs was higher in families with mutations leading to protein truncation than in families with missense mutations (75% vs 57%, respectively; p = 0.04). Furthermore, missense mutations within MCR-1, but not MCR-2, conferred genetic susceptibility to RCC. Autosomal Recessive Familial Erythrocytosis 2 Inheritance of germline mutations in both VHL alleles was found by {3:Ang et al. (2002)} and by others ({74:Pastore et al., 2003}; {78:Percy et al., 2002}) as the cause of autosomal recessive familial erythrocytosis (ECYT2, {263400}; see {608537.0019}). The VHL protein plays an important role in hypoxia sensing. It binds to hydroxylated HIF1-alpha and serves as a recognition component of an E3 ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF1-alpha forms a heterodimer with HIF1-beta and leads to increased transcription of hypoxia-inducible genes, including EPO. {74:Pastore et al. (2003)} reported 7 erythrocytosis patients with VHL mutations in both alleles ({608537.0021}-{608537.0024}). Two Danish sibs and an American boy were homozygous for the R200W mutation ({608537.0019}). Three unrelated white Americans were compound heterozygous for R200W and another VHL mutation: L188V ({608537.0014}) in 2 and P192A ({608537.0023}) in the third. Additionally, a Croatian boy was homozygous for an H191D mutation ({608537.0024}). {74:Pastore et al. (2003)} stated that they had not observed VHL syndrome-associated tumors in subjects with erythrocytosis or their heterozygous relatives. They found that up to half of the consecutive patients with apparent congenital erythrocytosis and increased serum EPO ({133170}) whom they had examined had mutations of both VHL alleles. They concluded that VHL mutations are the most frequent cause of recessive congenital erythrocytosis and define a class of disorders due to augmented hypoxia sensing. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {29:Gemmill et al. (2002)} isolated the Drosophila homolog of TRC8 ({603046}) and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either Drosophila Trc8 or Vhl resulted in an identical ventral midline defect. Direct interaction between Trc8 and Vhl in Drosophila was confirmed by GST-pull-down and coimmunoprecipitation experiments. {29:Gemmill et al. (2002)} found that in Drosophila, overexpression of Trc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Human JAB1 ({604850}) localization was dependent on VHL mutant status. Thus, the VHL, TRC8, and JAB1 proteins appear to be linked both physically and functionally, and all 3 may participate in the development of kidney cancer. {19:Ding et al. (2006)} used the Cre-loxP system to delete the Vhl gene from podocytes in the glomerular basement membrane of mice. At about 4 weeks of age, the mice developed rapidly progressive renal disease with hematuria, proteinuria, and renal failure with crescentic glomerulonephritis with prominent segmental fibrin deposition and fibrinoid necrosis. No immune deposits were present; the phenotype was similar to human 'pauci-immune' rapidly progressive glomerulonephritis (RPGN). Gene expression profiling showed increased expression of the HIF target gene Cxcr4 ({162643}) in glomeruli from both mice and humans with RPGN. Treatment of the mice with a Cxcr4 antibody resulted in clinical improvement, and isolated overexpression of Cxcr4 was sufficient to cause glomerular disease. {19:Ding et al. (2006)} hypothesized that upregulation of Cxcr4 allowed terminally differentiated podocytes to reenter the cell cycle, proliferate, and form cellular crescents. {38:Hickey et al. (2007)} found that mice homozygous for the Chuvash polycythemia-associated VHL mutation (R200W; {608537.0019}) developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A ({603349}) and of key target genes, including EPO, VEGF ({192240}), GLUT1 ({138140}), and PAI1 ({173360}), that contribute to polycythemia. Using immunofluorescence microscopy, {105:Zehetner et al. (2008)} found that Vhl was expressed in mouse insulin-producing pancreatic beta cells. Conditional inactivation of Vhl in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhl-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminated in impaired systemic glucose tolerance. Vhl deletion was associated with upregulation of Hif1a and the glucose transporter Glut1, an Hif1a target gene. Combined deletion of Vhl and Hif1a rescued the defects due to Vhl deletion alone, implying that they resulted from Hif1a activation. {53:Lee et al. (2009)} generated transgenic mouse embryonic stem cells with the homozygous VHL type 2B mutation R167Q ({608537.0005}). Mutant cells had preserved regulation of both HIF-alpha factors with slightly greater normotoxic dysregulation of HIF2-alpha. R167Q-derived teratomas had a growth advantage and showed hemangioma formation. Homozygous mice were embryonic lethal due to placental failure, and heterozygous mice developed renal cysts and were predisposed to the carcinogen-promoted renal carcinoma. textSectionName animalModel geneMapExists true editHistory carol : 04/22/2013 terry : 4/4/2013 carol : 8/5/2011 wwang : 8/5/2011 ckniffin : 8/3/2011 alopez : 1/10/2011 wwang : 11/10/2010 ckniffin : 10/28/2010 wwang : 9/3/2010 ckniffin : 8/30/2010 alopez : 4/14/2010 carol : 12/23/2009 ckniffin : 12/15/2009 wwang : 9/29/2009 alopez : 6/22/2009 terry : 6/16/2009 wwang : 6/11/2009 terry : 6/8/2009 terry : 6/3/2009 mgross : 4/3/2009 mgross : 4/3/2009 terry : 4/1/2009 carol : 9/23/2008 terry : 9/10/2008 terry : 6/6/2008 mgross : 5/29/2008 terry : 5/28/2008 wwang : 5/16/2008 ckniffin : 3/13/2008 mgross : 2/28/2008 terry : 1/14/2008 wwang : 8/13/2007 terry : 8/9/2007 terry : 8/1/2007 wwang : 7/12/2007 wwang : 11/13/2006 terry : 11/3/2006 ckniffin : 11/1/2006 wwang : 8/21/2006 wwang : 8/18/2006 ckniffin : 8/14/2006 mgross : 6/14/2006 terry : 6/13/2006 carol : 5/24/2006 ckniffin : 5/23/2006 wwang : 4/24/2006 ckniffin : 4/17/2006 alopez : 3/29/2006 terry : 3/28/2006 terry : 2/3/2006 carol : 1/12/2006 ckniffin : 1/6/2006 tkritzer : 10/6/2004 terry : 9/30/2004 tkritzer : 9/2/2004 terry : 8/24/2004 tkritzer : 6/3/2004 ckniffin : 6/2/2004 carol : 3/23/2004 ckniffin : 3/23/2004 ckniffin : 3/23/2004 ckniffin : 3/19/2004 dateCreated Wed, 17 Mar 2004 03:00:00 EST creationDate Cassandra L. Kniffin : 3/17/2004 epochUpdated 1366614000 dateUpdated Mon, 22 Apr 2013 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1002/ajmg.a.31116 publisherName John Wiley & Sons, Inc. title The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma. mimNumber 608537 referenceNumber 1 publisherAbbreviation Wiley pubmedID 16502427 source Am. J. Med. Genet. 140A: 685-690, 2006. authors Abbott, M.-A., Nathanson, K. L., Nightingale, S., Maher, E. R., Greenstein, R. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://archopht.ama-assn.org/cgi/pmidlookup?view=long&pmid=11709017 publisherName HighWire Press title Molecular characterization and ophthalmic investigation of a large family with type 2A von Hippel-Lindau disease. mimNumber 608537 referenceNumber 2 publisherAbbreviation HighWire pubmedID 11709017 source Arch. Ophthal. 119: 1659-1665, 2001. authors Allen, R. C., Webster, A. R., Sui, R., Brown, J., Taylor, C. M., Stone, E. M. pubmedImages false publisherUrl http://highwire.stanford.edu source Blood Cell Molec. Dis. 28: 57-62, 2002. mimNumber 608537 authors Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T. title Endemic polycythemia in Russia: mutation in the VHL gene. referenceNumber 3 articleUrl http://dx.doi.org/10.1038/ng1019 publisherName Nature Publishing Group title Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. mimNumber 608537 referenceNumber 4 publisherAbbreviation NPG pubmedID 12415268 source Nature Genet. 32: 614-621, 2002. authors Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., Maxwell, P. H., Stockton, D. W., Semenza, G. L., Prchal, J. T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=11483638 publisherName HighWire Press title VHL c.505 T-C mutation confers a high age related penetrance but no increased overall mortality. mimNumber 608537 referenceNumber 5 publisherAbbreviation HighWire pubmedID 11483638 source J. Med. Genet. 38: 508-514, 2001. authors Bender, B. U., Eng, C., Olschewski, M., Berger, D. P., Laubenberger, J., Altehofer, C., Kirste, G., Orszagh, M., van Velthoven, V., Miosczka, H., Schmidt, D., Neumann, H. P. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11134110 publisherName HighWire Press title Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. mimNumber 608537 referenceNumber 6 publisherAbbreviation HighWire pubmedID 11134110 source J. Clin. Endocr. Metab. 85: 4568-4574, 2000. authors Bender, B. U., Gutsche, M., Glasker, S., Muller, B., Kirste, G., Eng, C., Neumann, H. P. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9399847 publisherName HighWire Press title Software and database for the analysis of mutations in the VHL gene. mimNumber 608537 referenceNumber 7 publisherAbbreviation HighWire pubmedID 9399847 source Nucleic Acids Res. 26: 256-258, 1998. authors Beroud, C., Joly, D., Gallou, C., Staroz, F., Orfanelli, M. T., Junien, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19991119)87:2<163::AID-AJMG7>3.0.CO;2-A publisherName John Wiley & Sons, Inc. title Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene. mimNumber 608537 referenceNumber 8 publisherAbbreviation Wiley pubmedID 10533030 source Am. J. Med. Genet. 87: 163-167, 1999. authors Bradley, J. F., Collins, D. L., Schimke, R. N., Parrott, H. N., Rothberg, P. G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. mimNumber 608537 referenceNumber 9 pubmedID 7759077 source Hum. Genet. 95: 551-556, 1995. authors Brauch, H., Kishida, T., Glavac, D., Chen, F., Pausch, F., Hofler, H., Latif, F., Lerman, M. I., Zbar, B., Neumann, H. P. H. pubmedImages false articleUrl http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=15642664 publisherName HighWire Press title Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. mimNumber 608537 referenceNumber 10 publisherAbbreviation HighWire pubmedID 15642664 source Haematologica 90: 19-24, 2005. authors Cario, H., Schwarz, K., Jorch, N., Kyank, U., Petrides, P. E., Schneider, D. T., Uhle, R., Debatin, K.-M., Kohne, E. pubmedImages false publisherUrl http://highwire.stanford.edu title Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. mimNumber 608537 referenceNumber 11 pubmedID 7728151 source Hum. Mutat. 5: 66-75, 1995. authors Chen, F., Kishida, T., Yao, M., Hustad, T., Glavac, D., Dean, M., Gnarra, J. R., Orcutt, M. L., Duh, F. M., Glenn, G., Green, J., Hsia, Y. E., Lamiell, J., Li, H., Wei, M. H., Schmidt, L., Tory, K., Kuzman, I., Stackhouse, T., Latif, F., Linehan, W. M., Lerman, M., Zbar, B. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8863170 publisherName HighWire Press title Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A. mimNumber 608537 referenceNumber 12 publisherAbbreviation HighWire pubmedID 8863170 source J. Med. Genet. 33: 716-717, 1996. authors Chen, F., Slife, L., Kishida, T., Mulvihill, J., Tisherman, S. E., Zbar, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11331613 publisherName HighWire Press title Contrasting effects on HIF-1-alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. mimNumber 608537 referenceNumber 13 publisherAbbreviation HighWire pubmedID 11331613 source Hum. Molec. Genet. 10: 1029-1038, 2001. authors Clifford, S. C., Cockman, M. E., Smallwood, A. C., Mole, D. R., Woodward, E. R., Maxwell, P. H., Ratcliffe, P. J., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8634692 publisherName HighWire Press title Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. mimNumber 608537 referenceNumber 14 publisherAbbreviation HighWire pubmedID 8634692 source Hum. Molec. Genet. 4: 2233-2237, 1995. authors {Clinical Research Group for VHL in Japan} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1254 publisherName Nature Publishing Group title Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein. mimNumber 608537 referenceNumber 15 publisherAbbreviation NPG pubmedID 14556007 source Nature Genet. 35: 229-237, 2003. authors Corn, P. G., McDonald, E. R., III, Herman, J. G., El-Deiry, W. S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8592333 publisherName HighWire Press title Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. mimNumber 608537 referenceNumber 16 publisherAbbreviation HighWire pubmedID 8592333 source J. Med. Genet. 32: 885-886, 1995. authors Crossey, P. A., Eng, C., Ginalska-Malinowska, M., Lennard, T. W. J., Wheeler, D. C., Ponder, B. A. J., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu title Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. mimNumber 608537 referenceNumber 17 pubmedID 8270255 source Hum. Genet. 93: 53-58, 1994. authors Crossey, P. A., Foster, K., Richards, F. M., Phipps, M. E., Latif, F., Tory, K., Jones, M. H., Bentley, E., Kumar, R., Lerman, M. I., Zbar, B., Affara, N. A., Ferguson-Smith, M. A., Maher, E. R. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7987306 publisherName HighWire Press title Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. mimNumber 608537 referenceNumber 18 publisherAbbreviation HighWire pubmedID 7987306 source Hum. Molec. Genet. 3: 1303-1308, 1994. authors Crossey, P. A., Richards, F. M., Foster, K., Green, J. S., Prowse, A., Latif, F., Lerman, M. I., Zbar, B., Affara, N. A., Ferguson-Smith, M. A., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nm1460 publisherName Nature Publishing Group title Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. mimNumber 608537 referenceNumber 19 publisherAbbreviation NPG pubmedID 16906157 source Nature Med. 12: 1081-1087, 2006. authors Ding, M., Cui, S., Li, C., Jothy, S., Haase, V., Steer, B. M., Marsden, P. A., Pippin, J., Shankland, S., Rastaldi, M. P., Cohen, C. D., Kretzler, M., Quaggin, S. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7604013 publisherName HighWire Press title Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. mimNumber 608537 referenceNumber 20 publisherAbbreviation HighWire pubmedID 7604013 source Proc. Nat. Acad. Sci. 92: 6459-6463, 1995. authors Duan, D. R., Humphrey, J. S., Chen, D. Y. T., Weng, Y., Sukegawa, J., Lee, S., Gnarra, J. R., Linehan, W. M., Klausner, R. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=7660122 publisherName HighWire Press title Inhibition of transcription elongation by the VHL tumor suppressor protein. mimNumber 608537 referenceNumber 21 publisherAbbreviation HighWire pubmedID 7660122 source Science 269: 1402-1406, 1995. authors Duan, D. R., Pause, A., Burgess, W. H., Aso, T., Chen, D. Y. T., Garrett, K. P., Conaway, R. C., Conaway, J. W., Linehan, W. M., Klausner, R. D. pubmedImages false publisherUrl http://highwire.stanford.edu source J. Clin. Genet. 32: 934-937, 1995. mimNumber 608537 authors Eng, C., Crossey, P. A., Mulligan, L. M., Healey, C. S., Houghton, C., Prowse, A., Chew, S. L., Dahia, P. L. M., O'Riordan, J. L. H., Toledo, S. P. A., Smith, D. P., Maher, E. R., Ponder, B. A. J. title Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. referenceNumber 22 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(01)00507-4 publisherName Elsevier Science title C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. mimNumber 608537 referenceNumber 23 publisherAbbreviation ES pubmedID 11595184 source Cell 107: 43-54, 2001. authors Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., Tian, Y.-M., Masson, N., Hamilton, D. L., Jaakkola, P., Barstead, R., Hodgkin, J., Maxwell, P. H., Pugh, C. W., Schofield, C. J., Ratcliffe, P. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=9353177 publisherName HighWire Press title Human cancer syndromes: clues to the origin and nature of cancer. mimNumber 608537 referenceNumber 24 publisherAbbreviation HighWire pubmedID 9353177 source Science 278: 1043-1050, 1997. authors Fearon, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu source Molec. Cell 1051-1061, 1999. mimNumber 608537 authors Feldman, D. E., Thulasiraman, V., Ferreyra, R. G., Frydman, J. title Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC. referenceNumber 25 articleUrl http://dx.doi.org/10.1002/humu.20082 publisherName John Wiley & Sons, Inc. title Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. mimNumber 608537 referenceNumber 26 publisherAbbreviation Wiley pubmedID 15300849 source Hum. Mutat. 24: 215-224, 2004. Note: Erratum: Hum. Mutat. 24: 435-436, 2004. authors Gallou, C., Chauveau, D., Richard, S., Joly, D., Giraud, S., Olschwang, S., Martin, N., Saquet, C., Chretien, Y., Mejean, A., Correas, J.-M., Benoit, G., Colombeau, P., Grunfeld, J.-P., Junien, C., Beroud, C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:6<464::AID-HUMU6>3.0.CO;2-A publisherName John Wiley & Sons, Inc. title Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC. mimNumber 608537 referenceNumber 27 publisherAbbreviation Wiley pubmedID 10408776 source Hum. Mutat. 13: 464-475, 1999. authors Gallou, C., Joly, D., Mejean, A., Staroz, F., Martin, N., Tarlet, G., Orfanelli, M. T., Bouvier, R., Droz, D., Chretien, Y., Marechal, J. M., Richard, S., Junien, C., Beroud, C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Molecular diagnosis of von Hippel-Lindau disease in a kindred with a predominance of familial phaeochromocytoma. mimNumber 608537 referenceNumber 28 pubmedID 9156047 source Clin. Endocr. 46: 359-363, 1997. authors Garcia, A., Matias-Guiu, X., Cabezas, R., Chico, A., Prat, J., Baiget, M., De Leiva, A. pubmedImages false articleUrl http://dx.doi.org/10.1038/sj.onc.1205437 publisherName Nature Publishing Group title The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. mimNumber 608537 referenceNumber 29 publisherAbbreviation NPG pubmedID 12032852 source Oncogene 21: 3507-3516, 2002. authors Gemmill, R. M., Bemis, L. T., Lee, J. P., Sozen, M. A., Baron, A., Zeng, C., Erickson, P. F., Hooper, J. E., Drabkin, H. A. pubmedImages false publisherUrl http://www.nature.com title Somatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis. mimNumber 608537 referenceNumber 30 pubmedID 8522307 source Hum. Path. 26: 1341-1346, 1995. authors Gilcrease, M. Z., Schmidt, L., Zbar, B., Truong, L., Rutledge, M., Wheeler, T. M. pubmedImages false articleUrl http://dx.doi.org/10.1002/ana.20704 publisherName John Wiley & Sons, Inc. title Second hit deletion size in von Hippel-Lindau disease. mimNumber 608537 referenceNumber 31 publisherAbbreviation Wiley pubmedID 16261628 source Ann. Neurol. 59: 105-110, 2006. authors Glasker, S., Sohn, T.-S., Okamoto, H., Li, J., Lonser, R. R., Oldfield, E. H., Vortmeyer, A. 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D., Marston Linehan, W. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=14726398 publisherName HighWire Press title Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. mimNumber 608537 referenceNumber 33 publisherAbbreviation HighWire pubmedID 14726398 source Blood 103: 3924-3932, 2004. authors Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., Polyakova, L. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=8550742 publisherName HighWire Press title Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene. mimNumber 608537 referenceNumber 34 publisherAbbreviation HighWire pubmedID 8550742 source J. Clin. Endocr. Metab. 81: 147-149, 1996. authors Gross, D. J., Avishai, N., Meiner, V., Filon, D., Zbar, B., Abeliovich, D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11171994 publisherName HighWire Press title Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. mimNumber 608537 referenceNumber 35 publisherAbbreviation HighWire pubmedID 11171994 source Proc. Nat. Acad. Sci. 98: 1583-1588, 2001. authors Haase, V. H., Glickman, J. N., Socolovsky, M., Jaenisch, R. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ncb899 publisherName Nature Publishing Group title Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. mimNumber 608537 referenceNumber 36 publisherAbbreviation NPG pubmedID 12510195 source Nature Cell Biol. 5: 64-70, 2003. authors Hergovich, A., Lisztwan, J., Barry, R., Ballschmieter, P., Krek, W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7937876 publisherName HighWire Press title Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinomas. mimNumber 608537 referenceNumber 37 publisherAbbreviation HighWire pubmedID 7937876 source Proc. Nat. Acad. Sci. 91: 9700-9704, 1994. authors Herman, J. G., Latif, F., Weng, Y., Lerman, M. I., Zbar, B., Liu, S., Samid, D., Duan, D.-S. R., Guarra, J. R., Linehan, W. M., Baylin, S. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI32614 publisherName Journal of Clinical Investigation title von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2-alpha signaling and splenic erythropoiesis. mimNumber 608537 referenceNumber 38 publisherAbbreviation JCI pubmedID 17992257 source J. Clin. Invest. 117: 3879-3889, 2007. authors Hickey, M. M., Lam, J. C., Bezman, N. A., Rathmell, W. K., Simon, M. C. pubmedImages true publisherUrl http://www.jci.org articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11331612 publisherName HighWire Press title von Hippel-Lindau, protein mutants linked to type 2C VHL disease preserve the ability to downregulated HIF. mimNumber 608537 referenceNumber 39 publisherAbbreviation HighWire pubmedID 11331612 source Hum. Molec. Genet. 10: 1019-1027, 2001. authors Hoffman, M. A., Ohh, M., Yang, H., Kico, J. M., Ivan, M., Kaelin, W. G., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature00767 publisherName Nature Publishing Group title Structural basis for the recognition of hydroxyproline in HIF-1-alpha by pVHL. mimNumber 608537 referenceNumber 40 publisherAbbreviation NPG pubmedID 12050673 source Nature 417: 975-978, 2002. authors Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., Jones, E. Y. pubmedImages false publisherUrl http://www.nature.com title Tumour suppression by the human von Hippel-Lindau gene product. mimNumber 608537 referenceNumber 41 pubmedID 7585187 source Nature Med. 1: 822-826, 1995. authors Iliopoulos, O., Kibel, A., Gray, S., Kaelin, W. 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J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=8069849 publisherName HighWire Press title Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. mimNumber 608537 referenceNumber 47 publisherAbbreviation HighWire pubmedID 8069849 source Cancer Res. 54: 4845-4847, 1994. authors Kanno, H., Kondo, K., Ito, S., Yamamoto, I., Fujii, S., Torigoe, S., Sakai, N., Hosaka, M., Shuin, T., Yao, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10850421 publisherName HighWire Press title Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation. mimNumber 608537 referenceNumber 48 publisherAbbreviation HighWire pubmedID 10850421 source Cancer Res. 60: 2820-2824, 2000. authors Kanno, H., Saljooque, F., Yamamoto, I., Hattori, S., Yao, M., Shuin, T., U, H.-S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1096-9896(199606)179:2<157::AID-PATH557>3.0.CO;2-S publisherName John Wiley & Sons, Inc. title Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. mimNumber 608537 referenceNumber 49 publisherAbbreviation Wiley pubmedID 8758207 source J. Path. 179: 157-161, 1996. authors Kenck, C., Wilhelm, M., Bugert, P., Staehler, G., Kovacs, G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=7660130 publisherName HighWire Press title Binding of the von Hippel-Lindau tumor suppressor protein to elongin B and C. mimNumber 608537 referenceNumber 50 publisherAbbreviation HighWire pubmedID 7660130 source Science 269: 1444-1446, 1995. authors Kibel, A., Iliopoulos, O., DeCaprio, J. A., Kaelin, W. G., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu title Identification of the promoter of the human von Hippel-Landau disease tumor suppressor gene. mimNumber 608537 referenceNumber 51 pubmedID 7784063 source Oncogene 10: 2185-2194, 1995. authors Kuzmin, I., Duh, F.-M., Latif, F., Geil, L., Zbar, B., Lerman, M. I. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8493574 publisherName HighWire Press title Identification of the von Hippel-Lindau disease tumor suppressor gene. mimNumber 608537 referenceNumber 52 publisherAbbreviation HighWire pubmedID 8493574 source Science 260: 1317-1320, 1993. authors Latif, F., Tory, K., Gnarra, J., Yao, M., Duh, F.-M., Orcutt, M. L., Stackhouse, T., Kuzmin, I., Modi, W., Geil, L., Schmidt, L., Zhou, F., Li, H., Wei, M. H., Chen, F., Glenn, G., Choyke, P., Walther, M. M., Weng, Y., Duan, D.-S. R., Dean, M., Glavac, D., Richards, F. M., Crossey, P. A., Ferguson-Smith, M. A., Le Paslier, D., Chumakov, I., Cohen, D., Chinault, A. C., Maher, E. R., Linehan, W. M., Zbar, B., Lerman, M. I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/onc.2009.12 publisherName Nature Publishing Group title VHL type 2B gene mutation moderates HIF dosage in vitro and in vivo. mimNumber 608537 referenceNumber 53 publisherAbbreviation NPG pubmedID 19252526 source Oncogene 28: 1694-1705, 2009. authors Lee, C. M., Hickey, M. M., Sanford, C. A., McGuire, C. G., Cowey, C. L., Simon, M. C., Rathmell, W. K. pubmedImages true publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8700833 publisherName HighWire Press title Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. mimNumber 608537 referenceNumber 54 publisherAbbreviation HighWire pubmedID 8700833 source Proc. Nat. Acad. Sci. 93: 1770-1775, 1996. authors Lee, S., Chen, D. Y. T., Humphrey, J. S., Gnarra, J. R., Linehan, W. M., Klausner, R. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=14604959 publisherName HighWire Press title The worldwide distribution of the VHL 598C-T mutation indicates a single founder effect. mimNumber 608537 referenceNumber 55 publisherAbbreviation HighWire pubmedID 14604959 source Blood 103: 1937-1940, 2004. authors Liu, E., Percy, M. J., Amos, C. I., Guan, Y., Shete, S., Stockton, D. W., McMullin, M. F., Polyakova, L. A., Ang, S. O., Pastore, Y. D., Jedlickova, K., Lappin, T. R. J., Gordeuk, V., Prchal, J. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7987327 publisherName HighWire Press title A novel mutation in the von Hippel-Lindau gene. mimNumber 608537 referenceNumber 56 publisherAbbreviation HighWire pubmedID 7987327 source Hum. Molec. Genet. 3: 1423-1424, 1994. authors Loeb, D. B., Pericak-Vance, M. A., Stajich, J. M., Vance, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201930 publisherName Nature Publishing Group title Allele-specific regulation of primary cilia function by the von Hippel-Lindau tumor suppressor. mimNumber 608537 referenceNumber 57 publisherAbbreviation NPG pubmedID 17912253 source Europ. J. Hum. Genet. 16: 73-78, 2008. authors Lolkema, M. P., Mans, D. A., Ulfman, L. H., Volpi, S., Voest, E. E., Giles, R. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=2352258 publisherName HighWire Press title Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. mimNumber 608537 referenceNumber 58 publisherAbbreviation HighWire pubmedID 2352258 source J. Med. Genet. 27: 311-314, 1990. authors Maher, E. R., Yates, J. R. W., Ferguson-Smith, M. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=11641274 publisherName HighWire Press title FIH-1: a novel protein that interacts with HIF-1-alpha and VHL to mediate repression of HIF-1 transcriptional activity. mimNumber 608537 referenceNumber 59 publisherAbbreviation HighWire pubmedID 11641274 source Genes Dev. 15: 2675-2686, 2001. authors Mahon, P. C., Hirota, K., Semenza, G. L. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10302 publisherName John Wiley & Sons, Inc. title Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. mimNumber 608537 referenceNumber 60 publisherAbbreviation Wiley pubmedID 14695531 source Hum. Mutat. 23: 40-46, 2004. authors Maranchie, J. K., Afonso, A., Albert, P. S., Kalyandrug, S., Phillips, J. L., Zhou, S., Peterson, J., Ghadimi, B. M., Hurley, K., Riss, J., Vasselli, J. R., Ried, T., Zbar, B., Choyke, P., Walther, M. M., Klausner, R. D., Linehan, W. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/20459 publisherName Nature Publishing Group title The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. mimNumber 608537 referenceNumber 61 publisherAbbreviation NPG pubmedID 10353251 source Nature 399: 271-275, 1999. authors Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., Ratcliffe, P. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=19372390 publisherName HighWire Press title Proteasomal regulation of the hypoxic response modulates aging in C. elegans. mimNumber 608537 referenceNumber 62 publisherAbbreviation HighWire pubmedID 19372390 source Science 324: 1196-1198, 2009. authors Mehta, R., Steinkraus, K. A., Sutphin, G. L., Ramos, F. J., Shamieh, L. S., Huh, A., Davis, C., Chandler-Brown, D., Kaeberlein, M. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=12004076 publisherName HighWire Press title Structure of an HIF-1-alpha-pVHL complex: hydroxyproline recognition in signaling. mimNumber 608537 referenceNumber 63 publisherAbbreviation HighWire pubmedID 12004076 source Science 296: 1886-1889, 2002. authors Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G., Jr., Pavletich, N. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=9271438 publisherName HighWire Press title The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. mimNumber 608537 referenceNumber 64 publisherAbbreviation HighWire pubmedID 9271438 source Molec . Cell. Biol. 17: 5629-5639, 1997. authors Mukhopadhyay, D., Knebelmann, B., Cohen, H. T., Ananth, S., Sukhatme, V. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa020152?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Germ-line mutations in nonsyndromic pheochromocytoma. mimNumber 608537 referenceNumber 65 publisherAbbreviation ATYPON pubmedID 12000816 source New Eng. J. Med. 346: 1459-1466, 2002. authors Neumann, H. P. H., Bausch, B., McWhinney, S. R., Bender, B. 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J., Volk, B., Kirste, G. pubmedImages false publisherUrl http://www.atypon.com/ title Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II. mimNumber 608537 referenceNumber 67 pubmedID 7563486 source JAMA 274: 1149-1151, 1995. authors Neumann, H. P. H., Eng, C., Mulligan, L. M., Glavac, D., Zauner, I., Ponder, B. A. J., Crossey, P. A., Maher, E. R., Brauch, H. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(91)91705-Y publisherName Elsevier Science title Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. mimNumber 608537 referenceNumber 68 publisherAbbreviation ES pubmedID 1673491 source Lancet 337: 1052-1054, 1991. authors Neumann, H. P. H., Wiestler, O. D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/humu.21219 publisherName John Wiley & Sons, Inc. title Genetic analysis of von Hippel-Lindau disease. mimNumber 608537 referenceNumber 69 publisherAbbreviation Wiley pubmedID 20151405 source Hum. Mutat. 31: 521-537, 2010. authors Nordstrom-O'Brien, M., van der Luijt, R. B., van Rooijen, E., van den Ouweland, A. M., Majoor-Krakauer, D. F., Lolkema, M. P., van Brussel, A., Voest, E. E., Giles, R. H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1096-9896(199606)179:2<151::AID-PATH556>3.0.CO;2-0 publisherName John Wiley & Sons, Inc. title Mutation of the von Hippel-Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. mimNumber 608537 referenceNumber 70 publisherAbbreviation Wiley pubmedID 8758206 source J. Path. 179: 151-156, 1996. authors Oberstrass, J., Reifenberger, G., Reifenberger, J., Wechsler, W., Collins, V. P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)80096-9 publisherName Elsevier Science title The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. mimNumber 608537 referenceNumber 71 publisherAbbreviation ES pubmedID 9651579 source Molec. Cell 1: 959-968, 1998. authors Ohh, M., Yauch, R. L., Lonergan, K. M., Whaley, J. M., Stemmer-Rachamimov, A. O., Louis, D. N., Gavin, B. J., Kley, N., Kaelin, W. 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D., Jelinek, J., Ang, S., Guan, Y., Liu, E., Jedlickova, K., Krishnamurti, L., Prchal, J. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9448273 publisherName HighWire Press title The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. mimNumber 608537 referenceNumber 76 publisherAbbreviation HighWire pubmedID 9448273 source Proc. Nat. Acad. Sci. 95: 993-998, 1998. authors Pause, A., Lee, S., Lonergan, K. M., Klausner, R. D. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12702509 publisherName HighWire Press title Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry. mimNumber 608537 referenceNumber 77 publisherAbbreviation HighWire pubmedID 12702509 source Blood 102: 1097-1099, 2003. authors Percy, M. J., McMullin, M. F., Jowitt, S. N., Potter, M., Treacy, M., Watson, W. H., Lappin, T. R. J. pubmedImages false publisherUrl http://highwire.stanford.edu source Blood 100: 660 only, 2002. mimNumber 608537 authors Percy, M. J., McMullin, M. F., Treacy, M., Potter, M., Watson, W. H., Jowitt, S. N., Lappin, T. R. J. title Identification of the Chuvash-type congenital polycythemia in patients of Asian and Western European ancestry. referenceNumber 78 articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=16210343 publisherName HighWire Press title Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. mimNumber 608537 referenceNumber 79 publisherAbbreviation HighWire pubmedID 16210343 source Blood 107: 514-519, 2006. authors Perrotta, S., Nobili, B., Ferraro, M., Migliaccio, C., Borriello, A., Cucciolla, V., Martinelli, V., Rossi, F., Punzo, F., Cirillo, P., Parisi, G., Zappia, V., Rotoli, B., Ragione, F. 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J., Krek, W. pubmedImages false publisherUrl http://www.nature.com title Familial pheochromocytoma. mimNumber 608537 referenceNumber 89 pubmedID 13985160 source JAMA 182: 152-156, 1962. authors Tisherman, S. E., Gregg, F. J., Danowski, T. S. pubmedImages false source Arch. Int. Med. 153: 2550-2556, 1993. mimNumber 608537 authors Tisherman, S. E., Tisherman, B. G., Tisherman, S. A., Dunmire, S., Levey, G. S., Mulvihill, J. J. title Three-decade investigation of familial pheochromocytoma: an allele of von Hippel-Lindau disease? referenceNumber 90 source Science 284: 602-604, 1999. mimNumber 608537 authors Tyers, M., Willems, A. R. title One ring to rule a superfamily of E3 ubiquitin ligases. referenceNumber 91 articleUrl http://dx.doi.org/10.1002/(SICI)1097-0215(19980729)77:3<337::AID-IJC5>3.0.CO;2-P publisherName John Wiley & Sons, Inc. title Germline mutations in the vhl gene in patients presenting with phaeochromocytomas. mimNumber 608537 referenceNumber 92 publisherAbbreviation Wiley pubmedID 9663592 source Int. J. Cancer. 77: 337-340, 1998. authors van der Harst, E., de Krijger, R. R., Dinjens, W. N. M., Weeks, L. E., Bonjer, H. J., Bruining, H. A., Lamberts, S. W. J., Koper, J. W. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=hhe49129 publisherName S. Karger AG, Basel, Switzerland title Localization of the gene responsible for familial benign polycythemia to chromosome 11q23. mimNumber 608537 referenceNumber 93 publisherAbbreviation Karger pubmedID 10364675 source Hum. Hered. 49: 129-132, 1999. authors Vasserman, N. N., Karzakova, L. M., Tverskaya, S. M., Saperov, V. N., Muchukova, O. M., Pavlova, G. P., Efimova, N. K., Vankina, N. N., Evgrafov, O. V. pubmedImages false publisherUrl http://www.karger.com source Baltimore, Md. 1/6/1995. mimNumber 608537 authors Vogelstein, B. title Personal Communication. referenceNumber 94 articleUrl http://dx.doi.org/10.1002/ana.10807 publisherName John Wiley & Sons, Inc. title Somatic mutations in VHL germline deletion kindred correlate with mild phenotype. mimNumber 608537 referenceNumber 95 publisherAbbreviation Wiley pubmedID 14755727 source Ann. Neurol. 55: 236-240, 2004. authors Wait, S. D., Vortmeyer, A. O., Lonser, R. R., Chang, D. T., Finn, M. A., Bhowmick, D. A., Pack, S. D., Oldfield, E. H., Zhuang, Z. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/nm.1922 publisherName Nature Publishing Group title Regulation of endocytosis via the oxygen-sensing pathway. mimNumber 608537 referenceNumber 96 publisherAbbreviation NPG pubmedID 19252501 source Nature Med. 15: 319-324, 2009. authors Wang, Y., Roche, O., Yan, M. S., Finak, G., Evans, A. J., Metcalf, J. L., Hast, B. E., Hanna, S. C., Wondergem, B., Furge, K. A., Irwin, M. S., Kim, W. Y., Teh, B. T., Grinstein, S., Park, M., Marsden, P. A., Ohh, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1172/JCI31581 publisherName Journal of Clinical Investigation title The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. mimNumber 608537 referenceNumber 97 publisherAbbreviation JCI pubmedID 17549257 source J. Clin. Invest. 117: 1616-1626, 2007. authors Wang, Y., Wan, C., Deng, L., Liu, X., Cao, X., Gilbert, S. R., Bouxsein, M. L., Faugere, M.-C., Guldberg, R. E., Gerstenfeld, L. C., Haase, V. H., Johnson, R. S., Schipani, E., Clemens, T. L. pubmedImages true publisherUrl http://www.jci.org articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=12414898 publisherName HighWire Press title VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline mutations P81S and L188V. mimNumber 608537 referenceNumber 98 publisherAbbreviation HighWire pubmedID 12414898 source J. Clin. Endocr. 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R., Frei, U., Eckardt, K.-U. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(07)00622-3 publisherName Elsevier Science title pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappa-B agonist Card9 by CK2. mimNumber 608537 referenceNumber 100 publisherAbbreviation ES pubmedID 17936701 source Molec. Cell 28: 15-27, 2007. authors Yang, H., Minamishima, Y. A., Yan, Q., Schlisio, S., Ebert, B. L., Zhang, X., Zhang, L., Kim, W. Y., Olumi, A. F., Kaelin, W. G., Jr. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/gcc.10123 publisherName John Wiley & Sons, Inc. title Somatic von Hippel-Lindau disease gene mutation in clear-cell renal carcinomas associated with end-stage renal disease/acquired cystic disease of the kidney. mimNumber 608537 referenceNumber 101 publisherAbbreviation Wiley pubmedID 12378530 source Genes Chromosomes Cancer 35: 359-364, 2002. authors Yoshida, M., Yao, M., Ishikawa, I., Kishida, T., Nagashima, Y., Kondo, K., Nakaigawa, N., Hosaka, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12097293 publisherName HighWire Press title Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. mimNumber 608537 referenceNumber 102 publisherAbbreviation HighWire pubmedID 12097293 source Cancer Res. 62: 3803-3811, 2002. authors Zatyka, M., da Silva, N. F., Clifford, S. C., Morris, M. R., Wiesener, M. S., Eckardt, K.-U., Houlston, R. S., Richards, F. M., Latif, F., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=12114475 publisherName HighWire Press title Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter. mimNumber 608537 referenceNumber 103 publisherAbbreviation HighWire pubmedID 12114475 source J. Med. Genet. 39: 463-472, 2002. authors Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3 publisherName John Wiley & Sons, Inc. title Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. mimNumber 608537 referenceNumber 104 publisherAbbreviation Wiley pubmedID 8956040 source Hum. Mutat. 8: 348-357, 1996. authors Zbar, B., Kishida, T., Chen, F., Schmidt, L., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., Brauch, H., Glavac, D., {and 14 others} pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=19056893 publisherName HighWire Press title pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells. mimNumber 608537 referenceNumber 105 publisherAbbreviation HighWire pubmedID 19056893 source Genes Dev. 22: 3135-3146, 2008. authors Zehetner, J., Danzer, C., Collins, S., Eckhardt, K., Gerber, P. A., Ballschmieter, P., Galvanovskis, J., Shimomura, K., Ashcroft, F. M., Thorens, B., Rorsman, P., Krek, W. pubmedImages true publisherUrl http://highwire.stanford.edu title Von Hippel-Lindau disease gene deletion detected in microdissected sporadic human colon carcinoma specimens. mimNumber 608537 referenceNumber 106 pubmedID 8617456 source Hum. Path. 27: 152-156, 1996. authors Zhuang, Z., Emmert-Buck, M. R., Roth, M. J., Gnarra, J., Linehan, W. M., Liotta, L. A., Lubensky, I. A. pubmedImages false seeAlso Herman et al. (1994); Neumann and Wiestler (1991)

entryList

entry status live allelicVariantExists true epochCreated 893055600 geneMap geneSymbols DJ1, PARK7 sequenceID 94 phenotypeMapList phenotypeMap phenotypeMimNumber 606324 mimNumber 602533 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 168600 phenotypeMappingKey 3 phenotype Parkinson disease 7, autosomal recessive early-onset chromosomeLocationStart 8021713 chromosomeSort 94 chromosomeSymbol 1 mimNumber 602533 confidence P mappingMethod Fd, R geneName Oncogene DJ-1 geneInheritance None computedCytoLocation 1p36.23 cytoLocation 1p36 transcript uc001aox.4 chromosomeLocationEnd 8045341 chromosome 1 contributors Patricia A. Hartz - updated : 1/7/2014 Patricia A. Hartz - updated : 10/10/2013 George E. Tiller - updated : 8/5/2013 Cassandra L. Kniffin - updated : 5/15/2013 Patricia A. Hartz - updated : 8/3/2012 Ada Hamosh - updated : 1/25/2011 Cassandra L. Kniffin - updated : 10/15/2009 George E. Tiller - updated : 11/18/2008 George E. Tiller - updated : 5/19/2008 Cassandra L. Kniffin - updated : 3/3/2008 Cassandra L. Kniffin - updated : 1/17/2008 George E. Tiller - updated : 10/31/2007 Patricia A. Hartz - updated : 12/1/2006 Paul J. Converse - updated : 11/9/2006 Cassandra L. Kniffin - updated : 3/6/2006 George E. Tiller - updated : 1/31/2006 Cassandra L. Kniffin - updated : 10/17/2005 Patricia A. Hartz - updated : 8/15/2005 Cassandra L. Kniffin - updated : 4/13/2005 Victor A. McKusick - updated : 12/9/2004 Cassandra L. Kniffin - updated : 6/7/2004 Cassandra L. Kniffin - updated : 12/30/2003 Victor A. McKusick - updated : 9/8/2003 Cassandra L. Kniffin - updated : 1/15/2003 clinicalSynopsisExists false mimNumber 602533 allelicVariantList allelicVariant status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET text In a consanguineous Dutch family with early-onset Parkinson disease (PARK7; {606324}), {6:Bonifati et al. (2003)} identified a 14-kb homozygous deletion in the DJ1 gene, which deleted exons 1 through 5 and 4 kb of sequence upstream of the open reading frame start. The deletion showed cosegregation with the disease in the 4 affected family members and was absent in over 1,220 chromosomes from the Dutch population. {12:Irrcher et al. (2010)} showed that this deletion mutation in DJ1 resulted in fragmented mitochondria and elevated markers of autophagy. mutations PARK7, 14-KB DEL number 1 clinvarAccessions RCV000007479;;1 status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET dbSnps rs28938172 text In a consanguineous Italian family with autosomal recessive early-onset Parkinson disease (PARK7; {606324}), {6:Bonifati et al. (2003)} identified a homozygous 497T-C transition in the DJ1 gene, resulting in a leu166-to-pro substitution (L166P) in the protein. The mutation showed cosegregation with the disease in 3 affected sibs and was absent in 320 chromosomes from the Italian population. A molecular model of the mutation was predicted to destabilize the terminal helix of the protein. {12:Irrcher et al. (2010)} showed that the L166P mutation in DJ1 resulted in fragmented mitochondria and elevated markers of autophagy. mutations PARK7, LEU166PRO number 2 clinvarAccessions RCV000007480;;1 status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET dbSnps rs74315351 text In an Ashkenazi Jewish patient with early-onset Parkinson disease ({606324}), {1:Abou-Sleiman et al. (2003)} identified a homozygous A-to-G change in exon 2 of the DJ1 gene, resulting in a met26-to-ile (M26I) substitution. The mutation was not present in more than 1,000 control chromosomes. mutations PARK7, MET26ILE number 3 clinvarAccessions RCV000007481;;1 status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET dbSnps rs74315352 text In an Afro-Caribbean patient with early-onset Parkinson disease ({606324}), {1:Abou-Sleiman et al. (2003)} identified a heterozygous mutation in exon 4 of the DJ1 gene, resulting in an asp149-to-ala (D149A) substitution. The mutation was not found in 750 white, 160 Ashkenazi, or 40 Afro-Caribbean chromosomes tested, suggesting that it is pathogenic, but the authors noted that they did not identify a second mutation in the DJ1 gene in this patient. {5:Bjorkblom et al. (2013)} found that DJ1 with the D149A substitution bound copper with higher affinity than wildtype DJ1. Mutant DJ1 also bound mercury. However, in contrast with wildtype DJ1, mutant Dj1 lacked the ability to protect mouse embryonic fibroblasts from copper- and mercury-induced cytotoxicity. mutations PARK7, ASP149ALA number 4 clinvarAccessions RCV000007482;;1 status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET dbSnps rs74315353 text Analyzing the DJ1 gene in 104 patients with early-onset Parkinson disease ({606324}), {11:Hering et al. (2004)} identified a homozygous 192G-C transversion, resulting in a glu64-to-asp (E64D) substitution, in 1 patient of Turkish ancestry. In the proband, a substantial reduction of dopamine uptake transporter (DAT; {126455}) binding was found in the striatum by PET scan, indicating a serious loss of presynaptic dopaminergic afferents. The proband's sister, also homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who was heterozygous for E64D. By crystallography, {11:Hering et al. (2004)} demonstrated that the E64D mutation does not alter the structure of the DJ1 protein; however, they observed a tendency toward decreased levels of the mutant protein when overexpressed in HEK293 or COS-7 cells. By immunocytochemistry, about 5% of the cells expressing E64D and up to 80% of the cells expressing the L166P mutation ({602533.0002}) displayed a predominant nuclear localization of the mutant DJ1 protein, in contrast to the homogeneous nuclear and cytoplasmic staining in HEK293 cells overexpressing wildtype DJ1. mutations PARK7, GLU64ASP number 5 clinvarAccessions RCV000007483;;1 status live name PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET dbSnps rs74315354,rs373653682 text In 3 affected sibs from a consanguineous southern Italian family with early-onset parkinsonism ({606324}), {4:Annesi et al. (2005)} identified double homozygosity for mutations in the DJ1 gene. One was a 3385G-A transition in exon 7, resulting in a glu163-to-lys (E163K) substitution, and the other was an 18-bp duplication (168-185dup) in the promoter region. Age at disease onset was 36, 35, and 24 years, respectively. Severe amyotrophic lateral sclerosis and cognitive impairment were prominent in 1 sib, while the other 2 had prominent parkinsonism and behavioral abnormalities. mutations PARK7, GLU163LYS AND 18-BP DUP number 6 clinvarAccessions RCV000007484;;1 status live name PARKINSON DISEASE, AUTOSOMAL RECESSIVE EARLY-ONSET, DIGENIC, PINK1/DJ1 dbSnps rs137853051 text In 2 Chinese sibs with early-onset Parkinson disease (see {605909}), {23:Tang et al. (2006)} identified compound heterozygosity for 2 mutations in 2 different genes: a 115G-T transversion in exon 3 of the DJ1 gene resulting in an ala39-to-ser (A39S) substitution in the third beta-sheet of the protein, and a P399L mutation ({608309.0014}) in the predicted kinase domain of the PINK1 gene. The DJ1 and PINK1 mutations were not observed in 240 and 568 control chromosomes, respectively, and both were located in highly conserved residues. The findings were consistent with digenic inheritance of Parkinson disease. A 42-year-old unaffected family member also carried both mutations, suggesting incomplete penetrance. Coimmunoprecipitation studies showed that both wildtype and mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of wildtype DJ1 increased steady-state levels of both mutant and wildtype PINK1, but mutant DJ1 decreased steady-state levels of both mutant and wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1 stability. Human neuroblastoma cells expressing either mutant PINK1 or DJ1 showed reduced viability following oxidative challenge with MPP compared to control cells, indicating that both proteins protect against cell stress. Coexpression of both wildtype proteins resulted in a synergistic increase in cell viability against MPP-induced stress. In addition, coexpression of both mutant proteins significantly increased susceptibility of cells to death, compared to either mutant alone. These findings indicated that DJ1 and PINK1 function collaboratively. mutations PARK7, ALA39SER number 7 clinvarAccessions RCV000007485;;1 prefix * titles alternativeTitles PARK7 GENE; PARK7 preferredTitle ONCOGENE DJ1; DJ1 textSectionList textSection textSectionTitle Description textSectionContent DJ1, or PARK7, has pleiotropic function that includes roles as a chaperone with protease activity, a transcriptional regulator, and an antioxidant scavenger and redox sensor. DJ1 is also involved in tumorigenesis and in maintaining mitochondrial homeostasis (summary by {19:Ottolini et al., 2013}). textSectionName description textSectionTitle Cloning textSectionContent {18:Nagakubo et al. (1997)} used yeast 2-hybrid screening of a HeLa cell library to clone a cDNA that encodes a novel 189-amino acid protein, termed DJ1. Northern blot analysis revealed that DJ1 is ubiquitously expressed as a 1.0-kb transcript. Western blot analysis and immunofluorescence showed that the DJ1 protein is present in both nuclei and cytoplasm of HeLa cells. After addition of serum to cells, DJ1 expression increased and the protein translocated from the cytoplasm to nuclei. A search of the GenBank protein database revealed that DJ1 has approximately 40% identity to the 198-amino acid protein product of the E. coli thiazole monophosphate biosynthesis (ThiJ) gene. A homolog also exists in the nematode C. elegans. Northern blot analysis by {6:Bonifati et al. (2003}) showed ubiquitous expression of the DJ1 transcript, particularly in liver, skeletal muscle, and kidney. In the brain, expression was also ubiquitous, with higher levels of the transcript in subcortical regions, such as the caudate nucleus, the thalamus, the substantia nigra, and the hippocampus, that are more affected in parkinson disease (see MOLECULAR GENETICS). {28:Zhang et al. (2005)} generated highly specific antibodies to DJ1 protein and investigated the subcellular localization of endogenous DJ1 protein in both mouse brain tissues and human neuroblastoma cells. DJ1 was widely distributed and was highly expressed in brain. Cell fractionation and immunogold electron microscopy revealed an endogenous pool of DJ1 in mitochondrial matrix and intermembrane space. By screening a rat testis cDNA library, {24:Wagenfeld et al. (1998)} cloned a homologous gene in rats, called contraception associated protein-1 (CAP1), encoding a deduced protein that shares 95% and 91% sequence homology to mouse and human DJ1, respectively. A 1.6-kb transcript was detected in all rat tissues examined, with the highest level of expression in the testis. textSectionName cloning textSectionTitle Gene Structure textSectionContent {6:Bonifati et al. (2003)} reported that the DJ1 gene contains 8 exons spanning 24 kb. The first 2 exons (1A and 1B) are noncoding and alternatively spliced. textSectionName geneStructure textSectionTitle Mapping textSectionContent By genomic sequence analysis, {6:Bonifati et al. (2003)} mapped the DJ1 gene to chromosome 1p36. textSectionName mapping textSectionTitle Biochemical Features textSectionContent {25:Wilson et al. (2003)} reported the 3-dimensional structure of the DJ1 protein, determined at a resolution of 1.1 angstroms by x-ray crystallography. A highly conserved cysteine residue, which is catalytically essential in homologs of human DJ1, showed an extreme sensitivity to radiation damage and may be subject to other forms of oxidative modification as well. The structure suggested that the loss of function caused by the Parkinson-associated mutation L166P ({602533.0002}) is due to destabilization of the dimer interface. Taken together, the crystal structure of human DJ1 plus other observations suggested the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases. {9:Cookson (2003)} commented. {15:Macedo et al. (2003)} demonstrated that DJ1 protein formed a dimeric structure under physiologic conditions. Conversely, the L166P mutant protein showed a different elution profile in gel filtration assays as compared with wildtype, suggesting that L166P might form higher-order protein structures. In lymphoblasts from a parkinsonian patient who carried the homozygous mutation, the level of mutant protein was very low as compared with wildtype protein. Transfection experiments indicated that the mutant protein was rapidly degraded. {15:Macedo et al. (2003)} proposed that the rapid turnover and structural changes of the L166P mutant protein may be crucial in disease pathogenesis. {7:Chen et al. (2010)} reported that DJ1 is synthesized as a latent protease zymogen with low intrinsic proteolytic activity. DJ1 protease zymogen was activated by the removal of a 15-amino acid peptide at its C terminus. The activated DJ1 functioned as a cysteine protease with cys106 and his126 as the catalytic diad. Endogenous DJ1 in dopaminergic cells underwent C-terminal cleavage in response to mild oxidative stress, suggesting that DJ1 protease activation occurs in a redox-dependent manner. Moreover, the C-terminally cleaved form of DJ1 with activated protease function exhibited enhanced cytoprotective action against oxidative stress-induced apoptosis. The cytoprotective action of DJ1 was abolished by C106A and H126A mutations. {7:Chen et al. (2010)} proposed a role for DJ1 protease in cellular defense against oxidative stress. textSectionName biochemicalFeatures textSectionTitle Gene Function textSectionContent {18:Nagakubo et al. (1997)} found that the DJ1 gene has weak transforming ability in NIH 3T3 cells, but transformation by DJ1 is synergistically enhanced by cotransfection with HRAS ({190020}) or MYC ({190080}). {21:Takahashi et al. (2001)} showed that DJ1 bound strongly to PIASx-alpha ({603567}), a modulator of the nuclear androgen receptor (AR; {313700}), and colocalized with PIASx-alpha in the nuclei of monkey Cos-I cells. While PIASx repressed AR transcriptional activity to 40% of the original level, as measured with an androgen responsive element-luciferase reporter, addition of DJ1 abrogated this suppression. Furthermore, DJ1 bound to the AR-interacting domain of PIASx, suggesting that DJ1 antagonized PIASx function by absorbing it and interfering with its binding to AR. {21:Takahashi et al. (2001)} concluded that, in somatic cells, DJ1 functions as a positive regulator of AR. {20:Rizzu et al. (2004)} presented evidence suggesting that DJ1 colocalizes within a subset of pathologic tau (MAPT; {157140}) inclusions in a diverse group of neurodegenerative disorders known as tauopathies, and that the solubility of DJ1 is altered in association with its aggregation within these inclusions. {17:Moore et al. (2005)} showed that pathogenic mutant forms of DJ1 specifically but differentially associate with parkin ({602544}), an E3 ubiquitin ligase. Chemical crosslinking showed that pathogenic DJ1 mutants exhibited impairment in homodimer formation, suggesting that parkin may bind to monomeric DJ1. Parkin failed to specifically ubiquitinate and enhance the degradation of L166P ({602533.0002}) and M26I ({602533.0003}) mutant DJ1, but instead promoted their stability in cultured cells. Oxidative stress also promoted an interaction between DJ1 and parkin, but this did not result in the ubiquitination or degradation of DJ1. DJ1 levels were increased in the insoluble fraction of sporadic PD/DLB brains, but were reduced in the insoluble fraction of parkin-linked autosomal recessive juvenile-onset PD brains. The authors proposed that DJ1 and parkin may be linked in a common molecular pathway at multiple levels. In human dopaminergic neuronal cells, {27:Xu et al. (2005)} showed that the major interacting proteins with DJ1 were NRB54 (NONO; {300084}) and PSF (SFPQ; {605119}), which are multifunctional regulators of transcription and RNA metabolism. PD-associated DJ1 mutants exhibited decreased nuclear distribution and increased mitochondrial localization, resulting in diminished colocalization with coactivator NRB54 and repressor PSF. Wildtype DJ1 inhibited the transcriptional silencing activity of PSF unlike DJ1 mutants, and PSF induced neuronal apoptosis, which was reversed by wildtype DJ1 and to a lesser extent by PD-associated DJ1 mutants. RNAi-knockdown of DJ1 sensitized cells to PSF-induced apoptosis. Both DJ1 and NRB54 blocked oxidative stress and mutant alpha-synuclein (SNCA; {163890})-induced cell death. The findings showed that DJ1 is a neuroprotective transcriptional coactivator that may act in concert with NRB54 and PSF to regulate the expression of a neuroprotective genetic program. {27:Xu et al. (2005)} concluded that DJ1 mutations that impair transcriptional coactivator function can render dopaminergic neurons vulnerable to apoptosis and may contribute to the pathogenesis of Parkinson disease ({168600}). {13:Junn et al. (2005)} found that DJ1 overexpression in a human dopaminergic neuroblastoma cell line afforded modest protection against oxidative stress-induced cell death. A more robust cytoprotection was afforded by interaction of overexpressed DJ1 with the death protein DAXX ({603186}). DJ1 sequestered DAXX in the nucleus and prevented its translocation to the cytoplasm, where DAXX would normally activate its effector kinase, ASK1 (MAP3K5; {602448}), to trigger the death pathway. DJ1 carrying the L166P mutation did not interact with DAXX and was unable to protect cells from oxidative damage or DAXX/ASK1-induced apoptosis. {16:Meulener et al. (2006)} found that human DJ1 could rescue Drosophila lacking Dj1b, the fly homolog of DJ1, from oxidative insult, and that a conserved cysteine (cys104, which is analogous to human cys106) was critical for antioxidant function in vivo. SDS-PAGE analysis showed that DJ1 modification increased with age in flies, mice, and humans. In particular, an increase in acidic DJ1 isoforms with lower activity was observed. Modification of Dj1b increased dramatically in aged flies upon oxidative insult, and aged flies were more vulnerable to oxidative stress. {16:Meulener et al. (2006)} concluded that the risk factors of age and oxidative stress may regulate DJ1 protein activity, potentially contributing to Parkinson disease. Using small-interfering RNA (siRNA) to disrupt DJ1 expression in a human nonsmall cell lung carcinoma cell line, {8:Clements et al. (2006)} showed that DJ1 was required for the expression of several genes, including the NRF2 (NFE2L2; {600492})-regulated antioxidant enzyme NQO1 ({125860}). Without DJ1, NRF2 protein was unstable, and transcriptional responses were decreased both basally and after induction. DJ1 was indispensable for NRF2 stabilization by affecting NRF2 association with KEAP1 ({606016}), an inhibitor protein that promotes ubiquitination and degradation of NRF2. In human dopaminergic cells, {23:Tang et al. (2006)} demonstrated that wildtype DJ1 and PINK1 ({608309}), mutation in which causes PARK6 ({605909}), coimmunoprecipitate and interact functionally to protect cells from toxic oxidative MPP-induced cell death. Overexpression of both proteins resulted in a synergistic protective effect, and mutations in both proteins resulted in increased cell death compared to either mutant protein alone, suggesting a common mechanism. Evidence also suggested that DJ1 helps to stabilize PINK1. {26:Xiong et al. (2009)} demonstrated that parkin, PINK1, and DJ1 interact and form an approximately 200-kD functional ubiquitin E3 ligase complex in human primary neurons. PINK1 was shown to increase the activity of parkin, which degrades itself via the ubiquitin-proteasome system. Pathogenic PINK1 (G309D; {608309.0001}) did not promote ubiquitination and degradation of parkin or the parkin substrate synphilin-1 ({603779}) in transfected cells. Expression of DJ1 increased PINK1 expression, perhaps acting as a stabilizer. Overexpression of parkin substrates or heat shock treatment resulted in parkin accumulation in Pink1- or Dj1-deficient murine cells, and pathogenic parkin mutations resulted in a reduced ability to promote degradation of parkin substrates, all suggesting a decrease in E3 ubiquitin activity. {26:Xiong et al. (2009)} suggested that this complex promotes degradation of un- or misfolded proteins, including parkin, and that disruption of the activity of this complex leads to accumulation of abnormal proteins and increased susceptibility to oxidative stress, which is toxic to neurons and may lead to Parkinson disease. Using Dj1 -/- mouse cells, DJ1-linked PD patient lymphoblasts, and DJ1-knockdown human cell lines with appropriate controls, {12:Irrcher et al. (2010)} showed that loss of DJ1 resulted in mitochondrial fragmentation and sensitivity to oxidative damage. Reactive oxygen species (ROS) appeared to play a critical role in the defects, as mitochondria isolated from Dj1 -/- animals produced more ROS than controls and ROS scavengers rescued the phenotype. The aberrant mitochondrial phenotype was also reversed by expression of either wildtype human parkin or PINK. Dj1 -/- mouse cells and DJ1-linked PD patient lymphoblasts showed evidence of elevated autophagy, but not mitophagy. {19:Ottolini et al. (2013)} found that DJ1 was expressed at mitochondrial-associated membranes in the endoplasmic reticulum (ER) and that DJ1 maintained mitochondrial morphology and influenced mitochondrial Ca(2+) transients in stimulated HeLa cells. Knockdown of DJ1 resulted in mitochondrial fragmentation and decreased mitochondrial Ca(2+) uptake from the ER following stimulation. Conversely, overexpression of DJ1 augmented stimulation-induced mitochondrial Ca(2+) transients by increasing ER-mitochondrial communication. Overexpression of p53 in HeLa cells impaired the ability of mitochondria to accumulate Ca(2+) following stimulation, disrupted mitochondrial morphology, and reduced mitochondria-ER contact sites. DJ1 overexpression prevented p53 effects and reestablished ER-mitochondrial contacts. The effects of p53 on mitochondria did not require the transcriptional regulatory function of p53. Rescue of mitochondria by DJ1 was associated with enhanced degradation of p53, but it did not require DJ1 upregulation or DJ1 kinase activity. Overexpression of the mitochondrial profusion protein mitofusin-2 (MFN2; {608507}) also reversed the effects of p53 on mitochondria. {19:Ottolini et al. (2013)} concluded that DJ1 has a direct role in ER-mitochondria coupling and is essential to maintain mitochondrial structure and function. {5:Bjorkblom et al. (2013)} found that recombinant human DJ1 bound copper, mercury, and, more weakly, manganese, but not other ions tested. Dj1 also protected mouse embryonic fibroblasts (MEFs) against copper- and mercury-induced cytotoxicity. Exposure of MEFs to a nontoxic concentration of dopamine, together with copper or mercury, resulted in an almost immediate and dramatic surge of intracellular oxidation. The oxidative response was exacerbated in Dj1 -/- MEFs. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent In 2 consanguineous families from genetically isolated communities in the Netherlands and Italy with autosomal recessive early-onset Parkinson disease (PARK7; {606324}), {6:Bonifati et al. (2003)} identified 2 mutations in the DJ1 gene that cosegregated with the disease ({602533.0001} and {602533.0002}). Among 185 unrelated patients with early-onset Parkinson disease, {1:Abou-Sleiman et al. (2003)} identified 2 patients with mutations in the DJ1 gene ({602533.0003}-{602533.0004}); one was homozygous and the other was heterozygous. In addition, several variants were found in the DJ1 gene, which likely represented polymorphisms. The authors estimated that the frequency of DJ1 mutations in early-onset Parkinson disease is very low, at approximately 1%. No mutations in the DJ1 gene were identified in a cohort of later-onset sporadic cases of Parkinson disease. In a series of in vitro studies, {22:Takahashi-Niki et al. (2004)} found that mutant DJ1 proteins M26I ({602533.0003}), D149A ({602533.0004}), and L166P ({602533.0002}) formed heterodimers with wildtype DJ1. Mutant proteins M26I and L166P were unstable and were degraded by the proteasome system. Cell lines expressing the mutant M26I and L166P proteins showed reduced ability to eliminate exogenous hydrogen peroxide, indicating increased susceptibility to oxidative stress. In contrast, the mutant D149A protein showed increased stability compared to wildtype, and cells expressing the mutant D149A were resistant to hydrogen peroxide-induced cell death. {28:Zhang et al. (2005)} generated human neuroblastoma cells stably transfected with wildtype or mutant (e.g., M26I, L166P, and D149A) DJ1 constructs and performed mitochondrial fractionation and confocal colocalization imaging studies. When compared with wildtype and other mutants, the L166P mutant exhibited a largely reduced protein level. However, the pathogenic mutations did not alter the distribution of DJ1 to mitochondria. {28:Zhang et al. (2005)} concluded that DJ1 is an integral mitochondrial protein that may have important functions in regulating mitochondrial physiology. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {14:Kim et al. (2005)} found that mice with a targeted deletion of the Dj1 gene developed normally, had normal numbers of dopaminergic neurons in the substantia nigra, and showed no abnormal gross motor behavior up to 13 months of age. In vitro studies showed that primary cortical neurons from the Dj1-null mice exhibited increased sensitivity to oxidative stress compared to control cells. After challenge with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), Dj1-null mice showed a significant decrease in total activity and a greater loss of striatal dopaminergic neurons compared to control mice. Restoration of Dj1 expression in cell cultures or in Dj1-null mice resulted in a protective effect. Moreover, wildtype mice that received adenoviral delivery of Dj1 showed some resistance to MPTP-induced neuronal damage. {14:Kim et al. (2005)} concluded that Dj1 protects against neuronal oxidative stress, and that while loss of Dj1 alone may not be sufficient to produce parkinsonism, it may confer hypersensitivity to dopaminergic insults when challenged. In vitro and in vivo, {2:Aleyasin et al. (2007)} found that Dj1-null mice were significantly more susceptible to glutamate-induced neuronal excitotoxicity compared to controls. Expression of Dj1 provided protection. Further studies showed that the oxidation-sensitive cys106 residue was essential for neuronal protection from excitotoxicity. Dj1 expression decreased markers of oxidative stress after stroke insult in vivo, suggesting that Dj1 protects through alleviation of oxidative stress. {2:Aleyasin et al. (2007)} suggested that Dj1 may be important in other neuropathologic conditions besides Parkinson disease, and noted commonalities among different neuropathologies. {3:Andres-Mateos et al. (2007)} found that mice with targeted deletion of Dj1 exons 2 and 3 had no significant changes in the striatal dopaminergic system compared to wildtype mice. However, mitochondria isolated from the mutant mice contained a 2-fold increase in hydrogen peroxide associated with a decrease in mitochondrial aconitase (ACO2; {100850}). Older mutant mice showed a compensatory upregulation of mitochondrial superoxide dismutase (SOD1; {147450}) and glutathione peroxidase activity (see, e.g., GPX1; {138320}). Functional studies and mass spectrometry indicated that DJ1 is an atypical peroxiredoxin-like peroxidase that scavenges hydrogen peroxide through oxidation of cys106. Using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, {10:Guzman et al. (2010)} showed that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable substantia nigra pars compacta (SNc) dopaminergic neurons. The oxidant stress engaged defenses that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D ({601753}), which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ1 downregulated the expression of 2 uncoupling proteins, UCP4 (SLC25A27) and UCP5 (SLC25A14; {300242}), compromised calcium-induced uncoupling, and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, {10:Guzman et al. (2010)} suggested that their results pointed to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson disease ({168600}). textSectionName animalModel geneMapExists true editHistory mgross : 01/09/2014 mcolton : 1/7/2014 mgross : 10/10/2013 mgross : 10/10/2013 alopez : 8/5/2013 carol : 5/20/2013 ckniffin : 5/15/2013 carol : 10/8/2012 joanna : 10/4/2012 mgross : 8/8/2012 terry : 8/8/2012 terry : 8/3/2012 alopez : 1/31/2011 terry : 1/25/2011 carol : 7/12/2010 carol : 2/24/2010 wwang : 10/27/2009 ckniffin : 10/15/2009 ckniffin : 1/9/2009 wwang : 11/18/2008 wwang : 5/23/2008 terry : 5/19/2008 wwang : 3/19/2008 ckniffin : 3/3/2008 wwang : 3/3/2008 ckniffin : 1/17/2008 alopez : 11/5/2007 terry : 10/31/2007 wwang : 12/1/2006 mgross : 11/14/2006 terry : 11/9/2006 wwang : 3/10/2006 ckniffin : 3/6/2006 wwang : 2/7/2006 terry : 1/31/2006 wwang : 10/25/2005 ckniffin : 10/17/2005 wwang : 10/4/2005 ckniffin : 9/20/2005 ckniffin : 9/20/2005 mgross : 8/15/2005 wwang : 4/28/2005 wwang : 4/25/2005 ckniffin : 4/13/2005 tkritzer : 1/5/2005 terry : 12/9/2004 carol : 6/10/2004 ckniffin : 6/8/2004 ckniffin : 6/7/2004 tkritzer : 1/16/2004 ckniffin : 12/30/2003 cwells : 9/10/2003 terry : 9/8/2003 carol : 1/16/2003 ckniffin : 1/15/2003 dholmes : 5/12/1998 dholmes : 5/12/1998 dateCreated Mon, 20 Apr 1998 03:00:00 EDT creationDate Jennifer P. Macke : 4/20/1998 epochUpdated 1389254400 dateUpdated Thu, 09 Jan 2014 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1002/ana.10675 publisherName John Wiley & Sons, Inc. title The role of pathogenic DJ-1 mutations in Parkinson's disease. mimNumber 602533 referenceNumber 1 publisherAbbreviation Wiley pubmedID 12953260 source Ann. Neurol. 54: 283-286, 2003. authors Abou-Sleiman, P. M., Healy, D. G., Quinn, N., Lees, A. J., Wood, N. W. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18003894 publisherName HighWire Press title The Parkinson's disease gene DJ-1 is also a key regulator of stroke-induced damage. mimNumber 602533 referenceNumber 2 publisherAbbreviation HighWire pubmedID 18003894 source Proc. Nat. Acad. Sci. 104: 18748-18753, 2007. authors Aleyasin, H., Rousseaux, M. W. C., Phillips, M., Kim, R. H., Bland, R. J., Callaghan, S., Slack, R. S., During, M. J., Mak, T. W., Park, D. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17766438 publisherName HighWire Press title DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. mimNumber 602533 referenceNumber 3 publisherAbbreviation HighWire pubmedID 17766438 source Proc. Nat. Acad. Sci. 104: 14807-14812, 2007. authors Andres-Mateos, E., Perier, C., Zhang, L., Blanchard-Fillion, B., Greco, T. M., Thomas, B., Ko, H. S., Sasaki, M., Ischiropoulos, H., Przedborski, S., Dawson, T. M., Dawson, V. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.20666 publisherName John Wiley & Sons, Inc. title DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. mimNumber 602533 referenceNumber 4 publisherAbbreviation Wiley pubmedID 16240358 source Ann. Neurol. 58: 803-807, 2005. authors Annesi, G., Savettieri, G., Pugliese, P., D'Amelio, M., Tarantino, P., Ragonese, P., La Bella, V., Piccoli, T., Civitelli, D., Annesi, F., Fierro, B., Piccoli, F., Arabia, G., Caracciolo, M., Canadiano, I. C. C., Quattrone, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23792957 publisherName HighWire Press title Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. mimNumber 602533 referenceNumber 5 publisherAbbreviation HighWire pubmedID 23792957 source J. Biol. Chem. 288: 22809-22820, 2013. authors Bjorkblom, B., Adilbayeva, A., Maple-Grodem, J., Piston, D., Okvist, M., Xu, X. M., Brede, C., Larsen, J. P., Moller, S. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=12446870 publisherName HighWire Press title Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. mimNumber 602533 referenceNumber 6 publisherAbbreviation HighWire pubmedID 12446870 source Science 299: 256-259, 2003. authors Bonifati, V., Rizzu, P., van Baren, M. J., Schaap, O., Breedveld, G. J., Krieger, E., Dekker, M. C. J., Squitieri, F., Ibanez, P., Joosse, M., van Dongen, J. W., Vanacore, N., van Swieten, J. C., Brice, A., Meco, G., van Duijn, C. M., Oostra, B. A., Heutink, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20304780 publisherName HighWire Press title Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. mimNumber 602533 referenceNumber 7 publisherAbbreviation HighWire pubmedID 20304780 source Hum. Molec. Genet. 19: 2395-2408, 2010. authors Chen, J., Li, L., Chin, L.-S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17015834 publisherName HighWire Press title DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. mimNumber 602533 referenceNumber 8 publisherAbbreviation HighWire pubmedID 17015834 source Proc. Nat. Acad. Sci. 103: 15091-15096, 2006. authors Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., Ting, J. P.-Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12886009 publisherName HighWire Press title Crystallizing ideas about Parkinson's disease. mimNumber 602533 referenceNumber 9 publisherAbbreviation HighWire pubmedID 12886009 source Proc. Nat. Acad. Sci. 100: 9111-9113, 2003. authors Cookson, M. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature09536 publisherName Nature Publishing Group title Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. mimNumber 602533 referenceNumber 10 publisherAbbreviation NPG pubmedID 21068725 source Nature 468: 696-700, 2010. authors Guzman, J. N., Sanchez-Padilla, J., Wokosin, D., Kondapalli, J., Ilijic, E., Schumacker, P. T., Surmeier, D. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/humu.20089 publisherName John Wiley & Sons, Inc. title Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). mimNumber 602533 referenceNumber 11 publisherAbbreviation Wiley pubmedID 15365989 source Hum. Mutat. 24: 321-329, 2004. authors Hering, R., Strauss, K. M., Tao, X., Bauer, A., Woitalla, D., Mietz, E.-M., Petrovic, S., Bauer, P., Schaible, W., Muller, T., Schols, L., Klein, C., Berg, D., Meyer, P. T., Schulz, J. B., Wollnik, B., Tong, L., Kruger, R., Riess, O. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20639397 publisherName HighWire Press title Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. mimNumber 602533 referenceNumber 12 publisherAbbreviation HighWire pubmedID 20639397 source Hum. Molec. Genet. 19: 3734-3746, 2010. authors Irrcher, I., Aleyasin, H., Seifert, E. L., Hewitt, S. J., Chhabra, S., Phillips, M., Lutz, A. K., Rousseaux, M. W. C., Bevilacqua, L., Jahani-Asl, A., Callaghan, S., MacLaurin, J. G., {and 11 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15983381 publisherName HighWire Press title Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. mimNumber 602533 referenceNumber 13 publisherAbbreviation HighWire pubmedID 15983381 source Proc. Nat. Acad. Sci. 102: 9691-9696, 2005. authors Junn, E., Taniguchi, H., Jeong, B. S., Zhao, X., Ichijo, H., Mouradian, M. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15784737 publisherName HighWire Press title Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress. mimNumber 602533 referenceNumber 14 publisherAbbreviation HighWire pubmedID 15784737 source Proc. Nat. Acad. Sci. 102: 5215-5220, 2005. authors Kim, R. H., Smith, P. D., Aleyasin, H., Hayley, S., Mount, M. P., Pownall, S., Wakeham, A., You-Ten, A. J., Kalia, S. K., Horne, P., Westaway, D., Lozano, A. M., Anisman, H., Park, D. S., Mak, T. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12952867 publisherName HighWire Press title The DJ-1(L166P) mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes. mimNumber 602533 referenceNumber 15 publisherAbbreviation HighWire pubmedID 12952867 source Hum. Molec. Genet. 12: 2807-2816, 2003. authors Macedo, M. G., Anar, B., Bronner, I. F., Cannella, M., Squitieri, F., Bonifati, V., Hoogeveen, A., Heutink, P., Rizzu, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16894167 publisherName HighWire Press title Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. mimNumber 602533 referenceNumber 16 publisherAbbreviation HighWire pubmedID 16894167 source Proc. Nat. Acad. Sci. 103: 12517-12522, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 14978, 2006. authors Meulener, M. C., Xu, K., Thomson, L., Ischiropoulos, H., Bonini, N. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15525661 publisherName HighWire Press title Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. mimNumber 602533 referenceNumber 17 publisherAbbreviation HighWire pubmedID 15525661 source Hum. Molec. Genet. 14: 71-84, 2005. authors Moore, D. J., Zhang, L., Troncoso, J., Lee, M. K., Hattori, N., Mizuno, Y., Dawson, T. M., Dawson, V. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(97)96132-5 publisherName Elsevier Science title DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. mimNumber 602533 referenceNumber 18 publisherAbbreviation ES pubmedID 9070310 source Biochem. Biophys. Res. Commun. 231: 509-513, 1997. authors Nagakubo, D., Taira, T., Kitaura, H., Ikeda, M., Tamai, K., Iguchi-Ariga, S. M. M., Ariga, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23418303 publisherName HighWire Press title The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering. mimNumber 602533 referenceNumber 19 publisherAbbreviation HighWire pubmedID 23418303 source Hum. Molec. Genet. 22: 2152-2168, 2013. authors Ottolini, D., Cali, T., Negro, A., Brini, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.10782 publisherName John Wiley & Sons, Inc. title DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia. mimNumber 602533 referenceNumber 20 publisherAbbreviation Wiley pubmedID 14705119 source Ann. Neurol. 55: 113-118, 2004. authors Rizzu, P., Hinkle, D. A., Zhukareva, V., Bonifati, V., Severijnen, L.-A., Martinez, D., Ravid, R., Kamphorst, W., Eberwine, J. H., Lee, V. M.-Y., Trojanowski, J. Q., Heutink, P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11477070 publisherName HighWire Press title DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx-alpha to the receptor. mimNumber 602533 referenceNumber 21 publisherAbbreviation HighWire pubmedID 11477070 source J. Biol. Chem. 276: 37556-37563, 2001. authors Takahashi, K., Taira, T., Niki, T., Seino, C., Iguchi-Ariga, S. M. M., Ariga, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X04012094 publisherName Elsevier Science title Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients. mimNumber 602533 referenceNumber 22 publisherAbbreviation ES pubmedID 15219840 source Biochem. Biophys. Res. Commun. 320: 389-397, 2004. authors Takahashi-Niki, K., Niki, T., Taira, T., Iguchi-Ariga, S. M. M., Ariga, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16632486 publisherName HighWire Press title Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. mimNumber 602533 referenceNumber 23 publisherAbbreviation HighWire pubmedID 16632486 source Hum. Molec. Genet. 15: 1816-1825, 2006. authors Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., Zhu, Z., Ma, H., Pan, Q., Xia, J., Xia, K., Zhang, Z. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/ publisherName Elsevier Science title Molecular cloning and expression of rat contraception associated protein 1 (CAP1), a protein putatively involved in fertilization. mimNumber 602533 referenceNumber 24 publisherAbbreviation ES pubmedID 9792810 source Biochem. Biophys. Res. Commun. 251: 545-549, 1998. authors Wagenfeld, A., Gromoll, J., Cooper, T. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12855764 publisherName HighWire Press title The 1.1-Angstrom resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. mimNumber 602533 referenceNumber 25 publisherAbbreviation HighWire pubmedID 12855764 source Proc. Nat. Acad. Sci. 100: 9256-9261, 2003. authors Wilson, M. A., Collins, J. L., Hod, Y., Ringe, D., Petsko, G. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI37617 publisherName Journal of Clinical Investigation title Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. mimNumber 602533 referenceNumber 26 publisherAbbreviation JCI pubmedID 19229105 source J. Clin. Invest. 119: 650-660, 2009. authors Xiong, H., Wang, D., Chen, L., Choo, Y. S., Ma, H., Tang, C., Xia, K., Jiang, W., Ronai, Z., Zhuang, X., Zhang, Z. pubmedImages false publisherUrl http://www.jci.org articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15790595 publisherName HighWire Press title The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. mimNumber 602533 referenceNumber 27 publisherAbbreviation HighWire pubmedID 15790595 source Hum. Molec. Genet. 14: 1231-1241, 2005. authors Xu, J., Zhong, N., Wang, H., Elias, J. E., Kim, C. Y., Woldman, I., Pifl, C., Gygi, S. P., Geula, C., Yankner, B. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15944198 publisherName HighWire Press title Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. mimNumber 602533 referenceNumber 28 publisherAbbreviation HighWire pubmedID 15944198 source Hum. Molec. Genet. 14: 2063-2073, 2005. authors Zhang, L., Shimoji, M., Thomas, B., Moore, D. J., Yu, S.-W., Marupudi, N. I., Torp, R., Torgner, I. A., Ottersen, O. P., Dawson, T. M., Dawson, V. L. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 03961 nbkIDs NBK1223;;Parkinson Disease Overview refSeqAccessionIDs NG_008271.1 uniGenes Hs.419640 approvedGeneSymbols PARK7 nextGxDx true locusSpecificDBs http://www.LOVD.nl/PARK7;;PARK7 Parkinson's disease Mutation Database flybaseIDs FBgn0033885 dermAtlas false umlsIDs C1424222 gtr true geneIDs 11315 wormbaseIDs WBGene00015184,WBGene00016789 swissProtIDs Q99497 zfinIDs ZDB-GENE-041010-5 ensemblIDs ENSG00000116288,ENST00000377493 geneTests true ncbiReferenceSequences 530360488,530360490,183227677,183227676,530360486 genbankNucleotideSequences 34528108,164698131,34193707,148156663,71515079,211947946,52130609,148156664,30038759,16751470,21750104,511873846,50058383,5102616,2460317,312151781 proteinSequences 30038760,14198257,211947947,50058384,16751471,56404943,183227678,31543380,2460318,189065215,530360487,119591997,312151782 geneticsHomeReferenceIDs gene;;PARK7;;PARK7

entryList

entry status live allelicVariantExists true epochCreated 909648000 geneMap geneSymbols ABCC6, ARA, ABC34, MLP1, PXE, GACI2 sequenceID 10964 phenotypeMapList phenotypeMap phenotypeMimNumber 614473 mimNumber 603234 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 208000 phenotypeMappingKey 3 phenotype Arterial calcification, generalized, of infancy, 2 phenotypeMappingKey 3 mimNumber 603234 phenotypeInheritance Autosomal recessive phenotype Pseudoxanthoma elasticum phenotypeMimNumber 264800 phenotypeMappingKey 3 mimNumber 603234 phenotypeInheritance Autosomal dominant phenotype Pseudoxanthoma elasticum, forme fruste phenotypeMimNumber 177850 chromosomeLocationStart 16243421 chromosomeSort 181 chromosomeSymbol 16 mimNumber 603234 geneInheritance None confidence C mappingMethod A, Fd, LD geneName ATP-binding cassette, subfamily C, member 6 mouseMgiID MGI:1351634 mouseGeneSymbol Abcc6 computedCytoLocation 16p13.11 cytoLocation 16p13.1 transcript uc002den.4 chromosomeLocationEnd 16318082 chromosome 16 contributors Marla J. F. O'Neill - updated : 2/8/2012 Ada Hamosh - updated : 6/18/2010 Cassandra L. Kniffin - updated : 3/25/2010 Cassandra L. Kniffin - updated : 10/14/2009 Patricia A. Hartz - updated : 1/6/2009 George E. Tiller - updated : 10/28/2008 Patricia A. Hartz - updated : 8/5/2008 Victor A. McKusick - updated : 12/28/2007 Marla J. F. O'Neill - updated : 4/30/2007 Victor A. McKusick - updated : 3/6/2007 Patricia A. Hartz - updated : 2/28/2007 Patricia A. Hartz - updated : 2/28/2007 Matthew B. Gross - updated : 11/29/2006 Victor A. McKusick - edited : 9/21/2005 Cassandra L. Kniffin - updated : 4/1/2004 Jane Kelly - updated : 8/22/2003 Victor A. McKusick - updated : 3/10/2003 Victor A. McKusick - updated : 11/13/2002 Victor A. McKusick - updated : 10/17/2001 Victor A. McKusick - updated : 3/19/2001 Victor A. McKusick - updated : 5/30/2000 Ada Hamosh - updated : 5/22/2000 Jennifer P. Macke - updated : 12/2/1998 clinicalSynopsisExists false mimNumber 603234 allelicVariantList allelicVariant status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs72653706 text ---Pseudoxanthoma Elasticum In a large consanguineous Italian family segregating autosomal recessive pseudoxanthoma elasticum ({264800}), {33:Le Saux et al. (2000)} identified a C-to-T transition at nucleotide 3421 in exon 24 of the ABCC6 gene, resulting in an arg-to-ter substitution at codon 1141 (R1141X). All unaffected individuals but 1 were heterozygous carriers; affected individuals were homozygous for this mutation. This variant was not found in the control panel of 200 normal alleles and cosegregated in homozygous or compound heterozygous state with the PXE phenotype in families. This mutation was also identified in 5 unrelated pedigrees. R1141X was found in homozygous state in unrelated patients with autosomal recessive PXE from the United Kingdom and Belgium. Haplotype analysis of the PXE locus in families with the R1141X mutation revealed that this mutation was segregating with different haplotypes, suggesting that R1141X may be a recurrent mutation in ABCC6. Testing of cultured skin fibroblasts showed no ABCC6 mRNA in patients carrying the R1141X mutation from the large Italian pedigree. {7:Bergen et al. (2000)} identified this mutation in 2 families segregating autosomal dominant PXE ({177850}). In a family in which 2 brothers and a sister had PXE, {47:Ringpfeil et al. (2000)} demonstrated that the affected individuals were compound heterozygotes for the R1141X mutation and an R1268Q mutation ({603234.0011}). In a cohort of 101 unrelated patients with PXE, {30:Le Saux et al. (2001)} found that the R1141X mutant allele was present in 28.4% of European alleles and only 4.1% of U.S. alleles. Also, this nonsense mutation was unequally distributed among European countries. The frequency of homozygotes was in Hardy-Weinberg equilibrium in the European population. {17:Hu et al. (2003)} demonstrated a founder effect for the R1141X mutation in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. {17:Hu et al. (2003)} suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6. In the study of {53:Trip et al. (2002)}, the presence of a single R1141X mutation in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people. ---Generalized Arterial Calcification of Infancy 2 In 2 patients with generalized arterial calcification of infancy-2 (GACI2; {614473}), {40:Nitschke et al. (2012)} identified compound heterozygosity for 2 mutations in the ABCC6 gene. A French female infant with GACI who died at 6 weeks of age, who had calcification of the coronary arteries and other arteries, severe hypertension, and heart failure, was compound heterozygous for R1141X and R1314W ({603234.0006}). A 3-year-old Spanish boy with GACI who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, was compound heterozygous for R1141X and R518X ({603234.0027}). ---Pseudoxanthoma Elasticum, Forme Fruste, Digenic, ABCC6/GGCX In a woman and her sister with biopsy-confirmed PXE, {34:Li et al. (2009)} identified compound heterozygosity for the R1141X mutation and a mutation in the GGCX gene (V255M; {137167.0012}). Neither had evidence of a coagulopathy and the skin phenotype was mild (see {177850}), but skin biopsies showed undercarboxylated matrix gla proteins (MGP; {154870}) in the areas of abnormal mineralization. Since R1141X in the heterozygous state is usually not associated with clinical features, the findings suggested that the women had digenic inheritance of PXE. In contrast, 2 other family members who were compound heterozygous for R1141X and another mutation in the GGCX gene (S300F; {137167.0013}) had no signs of either disorder on clinical exam but refused further clinical testing. Plasma levels of undercarboxylated total MGP of the 2 clinically unaffected individuals were at the lower end of normal. Although the reasons for the lack of clinical findings in the 2 unaffected family members remained unclear, {34:Li et al. (2009)} concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE. mutations ABCC6, ARG1141TER number 1 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000023272;;1;;;RCV000006937;;1 status live name PSEUDOXANTHOMA ELASTICUM text ---Pseudoxanthoma Elasticum In patients with autosomal recessive pseudoxanthoma elasticum ({264800}) from 2 families, {33:Le Saux et al. (2000)} found that affected individuals carried a G-to-T transversion at the +1 position of intron 21 of the ABCC6 gene, affecting the donor splice site. One of the families was from the United Kingdom, and the other was from the United States. The family from the U.K. carried the R1141X mutation ({603234.0001}) on the other allele; in the American family, the other mutation was R1138Q ({603234.0003}). ---Generalized Arterial Calcification of Infancy 2 In a Canadian female infant with generalized arterial calcification of infancy (GACI2; {614473}), originally reported by {15:Glatz et al. (2006)}, who died at 6.5 weeks of age of myocardial infarction with calcification of the aorta and coronary, pulmonary, and renal arteries and occlusion of the right coronary artery, {40:Nitschke et al. (2012)} identified compound heterozygosity for 2 splice site mutations in the ABCC6 gene, a G-T transversion in intron 21 (IVS21+1G-T) and an IVS26-1G-A ({603234.0015}), both predicted to cause a frameshift resulting in a premature termination codon. mutations ABCC6, IVS21DS, G-T, +1 number 2 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000087145;;1;;;RCV000006938;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs60791294 text In a family with autosomal recessive pseudoxanthoma elasticum ({264800}), {33:Le Saux et al. (2000)} identified a G-to-A transition at nucleotide 3413 of the ABCC6 gene, resulting in an arginine-to-glutamine substitution at codon 1138 (R1138Q). This mutation was found in compound heterozygosity with the IVS21+1G-T mutation ({603234.0002}). In a so-called sporadic case of PXE, {47:Ringpfeil et al. (2000)} identified an R1138Q mutation in the ABCC6 gene in compound heterozygosity with the R1268 mutation ({603234.0011}). Arginine-1138 is the same codon as that affected in the R1138W mutation ({603234.0012}); in the latter mutation, the nucleotide change is 3412C-T. mutations ABCC6, ARG1138GLN number 3 clinvarAccessions RCV000006939;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63750427 text In a family with autosomal recessive pseudoxanthoma elasticum ({264800}), {33:Le Saux et al. (2000)} found affected individuals to be homozygous for a G-to-C transversion at nucleotide 3341 of the ABCC6 gene, resulting in an arg-to-pro substitution at codon 1114 (R1114P) in exon 24. This mutation was found in homozygosity. mutations ABCC6, ARG1114PRO number 4 clinvarAccessions RCV000006940;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs72664233 text In a patient thought to represent an isolated case of autosomal dominant pseudoxanthoma elasticum ({177850}), {33:Le Saux et al. (2000)} found a deletion of a T at nucleotide 3775 of the ABCC6 gene. This was a de novo mutation in the patient, and no mutations were found in the other allele of ABCC6 by screening using SSCP. {42:Plomp et al. (2009)} examined a group of 15 adults homozygous for the 3775delT mutation and 44 individuals heterozygous for this mutation from a genetically isolated population in the Netherlands. All participants filled out a questionnaire and underwent standardized dermatologic and ophthalmologic examinations with photography of skin and fundus abnormalities. Skin biopsies from affected skin or a predilection site and/or a scar were examined and compared with biopsies from controls. {42:Plomp et al. (2009)} found that skin abnormalities, ophthalmologic signs, and cardiovascular problems varied greatly among the 15 homozygous participants. There was no correlation among severity of skin, eyes, or cardiovascular abnormalities. None of the 44 heterozygous participants had any sign of pseudoxanthoma elasticum on dermatologic, histopathologic, and/or ophthalmologic examination, but 32% had cardiovascular disease. mutations ABCC6, 1-BP DEL, 3775T number 5 clinvarAccessions RCV000006941;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63750759 text ---Pseudoxanthoma Elasticum In a patient with autosomal recessive pseudoxanthoma elasticum ({264800}), {33:Le Saux et al. (2000)} identified a C-to-T transition at nucleotide 3940 of the ABCC6 gene, resulting in an arg-to-trp substitution at codon 1314 (R1314W). This mutation was found in homozygosity in one family. ---Generalized Arterial Calcification of Infancy 2 In a 5-year-old boy with generalized arterial calcification of infancy (GACI2; {614473}), {40:Nitschke et al. (2012)} identified homozygosity for the R1314W mutation. The boy was born as the first of dizygotic twins, and his twin brother was unaffected. The patient had calcification of the aorta and pulmonary, coronary, and renal arteries as well as other arteries, and stippled calcifications of proximal epiphyses of humeri, femora, pelvic cartilage, larynx, and mandible. He had severely decreased biventricular systolic function, marked cardiomegaly, and severe mitral insufficiency, as well as hypertension and respiratory insufficiency. Cerebral MRI revealed diffuse white matter disease, with cystic encephalomalacia, and laboratory analysis showed hyperbilirubinemia, anemia, and thrombocytopenia. {40:Nitschke et al. (2012)} also identified the R1314W mutation in compound heterozygosity in 2 unrelated GACI patients, a French female infant who died at 6 weeks of age and also carried an R1141X mutation ({603234.0001}), and an Afro-Caribbean male infant who died at 8 weeks of age with generalized arterial stenosis, myocardial infarction, and hypertension and also carried a 1-bp insertion (450insC; {603234.0028}) in exon 4 of the ABCC6 gene, predicted to result in a premature stop codon and a truncated protein. In addition, in a 3-year-old South African girl with GACI, {40:Nitschke et al. (2012)} identified only a heterozygous R1314W mutation, but noted that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their technique. In the South African child, onset of symptoms occurred at 2.5 years of age, and included calcification of the aorta, spleen, and pancreas, nephrocalcinosis, failure to thrive, hypertension, and heart failure. mutations ABCC6, ARG1314TRP number 6 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000023273;;1;;;RCV000006942;;1 status live name PSEUDOXANTHOMA ELASTICUM text In a large autosomal recessive pseudoxanthoma elasticum ({264800}) family, {7:Bergen et al. (2000)} identified the deletion of a T at nucleotide 3798 of the ABCC gene in homozygosity. This mutation results in a frameshift and premature chain termination. mutations ABCC6, 1-BP DEL, 3798T number 7 clinvarAccessions RCV000006941;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs387906352 text In 2 families segregating what was thought to be autosomal dominant pseudoxanthoma elasticum ({177850}), {7:Bergen et al. (2000)} identified a 4-bp insertion, AGAA, at nucleotide 4243 in exon 30. This insertion causes a frameshift resulting in the disruption of the Walker B motif and a protein longer by 24 amino acids. mutations ABCC6, 4-BP INS, 4243AGAA number 8 clinvarAccessions RCV000006944;;1 status live name PSEUDOXANTHOMA ELASTICUM text In a patient with pseudoxanthoma elasticum ({177850}), {7:Bergen et al. (2000)} identified a 22-basepair deletion from nucleotides 1967 through 1989 of the ABCC6 gene in heterozygosity. The other allele appeared to be wildtype. mutations ABCC6, 22-BP DEL number 9 clinvarAccessions RCV000006945;;1 status live name PSEUDOXANTHOMA ELASTICUM text In a patient with pseudoxanthoma elasticum ({177850}), {7:Bergen et al. (2000)} detected a large deletion encompassing the ABCC6 gene as well as the MYH11 ({160745}) and ABCC1 ({158343}) genes. The other allele appeared to be wildtype. mutations ABCC6, DEL number 10 clinvarAccessions RCV000006946;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs2238472 text {47:Ringpfeil et al. (2000)} found an arg1268-to-gln (R1268Q) mutation in compound heterozygous state in 3 presumably unrelated families with PXE ({264800}). In 2 families, the mutation was combined with R1141X ({603234.0001}); in 1 family, it was combined with R1138Q ({603234.0003}). In one of the families with PXE in which the R1141X mutation had been identified by {47:Ringpfeil et al. (2000)}, {14:Germain et al. (2000)} identified a 3803G-A transition in exon 27 of the ABCC6 cDNA, resulting in an R1268Q mutation. To their surprise, the R1268Q variant was found in homozygous state in the proband's unaffected husband. They investigated the R1268Q mutation and found the Q1268 allele at a relatively high frequency (0.19) in a control population of 62 Caucasians. Genotype frequencies were in Hardy-Weinberg equilibrium, and 3 healthy volunteers were homozygous for the Q1268 allele. R1268Q is thus a harmless polymorphism when present in homozygous state. mutations ABCC6, ARG1268GLN number 11 clinvarAccessions RCV000006948;;1;;;RCV000132640;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs28939701 text In a familial case of PXE ({264800}), {47:Ringpfeil et al. (2000)} found homozygosity for an arg1138-to-trp (R1138W) mutation in the ABCC6 gene due to a 3412C-T transition. The mutation was found in homozygous state in the proband's mother and in heterozygous state in her father, creating a pedigree pattern of pseudodominance. The same codon is involved in the R1138Q mutation due to a 3413G-A transition ({603234.0003}). {49:Ringpfeil et al. (2001)} discussed the same pedigree, derived from a consanguineous French Canadian PXE family. mutations ABCC6, ARG1138TRP number 12 clinvarAccessions RCV000006949;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs72653744 text {48:Ringpfeil et al. (2001)} studied the ABCC6 mutation in 4 multiplex families with PXE ({264800}) inherited in an autosomal recessive pattern. In each family, the proband was a compound heterozygote for a single-bp substitution mutation (3490C-T; arg1164 to ter) and a novel deletion of approximately 16.5 kb spanning the site of the single-bp substitution in trans (i.e., on the homologous chromosome 16) ({603234.0016}). In 2 of the families the single-nucleotide substitution was R1164X; in 1 it was R1141X ({603234.0001}); and in another it was a splice site mutation, 3736-1G-A ({603234.0015}). In all 4 families the patients were thought first to be homozygous for the nondeletion mutation. The deletion mutation was shown to extend from intron 22 to intron 29, resulting in out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA and causing elimination of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints were precisely the same in all 4 families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within introns 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism. mutations ABCC6, ARG1164TER number 13 clinvarAccessions RCV000006950;;1 status live name PSEUDOXANTHOMA ELASTICUM text See {603234.0013} and {48:Ringpfeil et al. (2001)}. mutations ABCC6, 1,213-BP DEL number 14 clinvarAccessions RCV000006951;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63750273 text See {603234.0013} and {48:Ringpfeil et al. (2001)}. See {603234.0002} and {40:Nitschke et al. (2012)}. mutations ABCC6, IVS26AS, G-A, -1 number 15 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000023274;;1;;;RCV000006952;;1 status live name PSEUDOXANTHOMA ELASTICUM text In a cohort of 101 unrelated patients with PXE ({264800}), {30:Le Saux et al. (2001)} identified a 16.4-kb deletion of the ABCC6 gene (deletion of exons 23-29) in 12.9% of mutant alleles. The frequency was very different in Europe and the United States, being 4.3% and 28.4%, respectively. The frequency of individuals homozygous for this mutation was observed to be in Hardy-Weinberg equilibrium in the United States. mutations ABCC6, 16.4-KB DEL number 16 clinvarAccessions RCV000006951;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs28939702 text In 17 Afrikaner families in South Africa with autosomal recessive pseudoxanthoma elasticum ({264800}), {31:Le Saux et al. (2002)} found that 53% of the PXE-associated alleles of the ABCC6 gene had a 4015C-T transition, which caused an arg1339-to-cys (R1339C) mutation. Haplotype analysis showed that the mutation was identical by descent in these families. mutations ABCC6, ARG1339CYS number 17 clinvarAccessions RCV000006954;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs72547524 text In a family in which PXE classified as 'definite' occurred in 2 generations, {43:Plomp et al. (2004)} detected an arg1459-to-cys substitution (R1459C) in the ABCC protein on 1 allele only. The authors considered the diagnosis of PXE definite if 2 of the following 3 criteria were present: yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body; typical histopathological changes in a skin biopsy after von Kossa staining; and the presence of peau d'orange, angioid streaks, or comet-like streaks in the retina. The mother of this family and one of her sons fulfilled all 3 criteria. {43:Plomp et al. (2004)} stated that the R1459C mutation might be one that could cause PXE in the heterozygous state ({177850}). In their review of families with putative autosomal dominant PXE, including this family and 2 others examined by them, the authors noted that they did not find a single family with definite PXE in 3 or more generations. {6:Bergen (2006)} stated that the family with the apparently heterozygous R1459C mutation studied by {43:Plomp et al. (2004)} remained 'an interesting puzzle and is perhaps the always existing 'exception to the rule'.' mutations ABCC6, ARG1459CYS number 18 clinvarAccessions RCV000006955;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63751325 text In a cohort of 122 unrelated patients with PXE ({264800}) from several countries, {30:Le Saux et al. (2001)} found a 3892G-T transversion in exon 28 of the ABCC6 gene that resulted in a val1298-to-phe (V1298F) substitution. The mutation was present in heterozygosity in 2 alleles from patients from the United States, for an allele frequency among 74 United States alleles of 2.7%. The mutation was not found in the European population. {20:Ilias et al. (2002)} showed that the V1298F mutation, localized to the C-terminal cytoplasmic domain of ABCC6, did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4. mutations ABCC6, VAL1298PHE number 19 clinvarAccessions RCV000006956;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63749856 text In a cohort of 122 unrelated patients with PXE ({264800}) from several countries, {30:Le Saux et al. (2001)} found a 3904G-A transition in exon 28 of the ABCC6 gene that resulted in a gly1302-to-arg (G1302R) amino acid substitution in the second intracellular nucleotide-binding domain. The mutation, present in homozygosity, occurred in a total of 4 alleles from patients from the United States, giving an allele frequency of 5.4% in a total of 74 United States alleles. It was not found in the European population. {20:Ilias et al. (2002)} showed that the G1302R mutation did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4. mutations ABCC6, GLY1302ARG number 20 clinvarAccessions RCV000006957;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63749823 text In a cohort of 122 unrelated patients with PXE ({264800}) from several countries, {30:Le Saux et al. (2001)} found a 3961G-A transition in exon 28 of the ABCC6 gene that resulted in a gly1321-to-ser (G1321S) substitution in the second intracellular nucleotide-binding domain. They found the mutation in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%. It was not found in the European population. {20:Ilias et al. (2002)} showed that the G1321S mutation did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4. mutations ABCC6, GLY1321SER number 21 clinvarAccessions RCV000006958;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63749796 text {10:Chassaing et al. (2004)} described a pedigree of PXE ({264800}) with pseudodominant inheritance. Two affected sibs carried 3 distinct mutations of the ABCC6 gene. The brother carried a 3712G-C transversion in exon 26 that resulted in an asp1238-to-his substitution (D1238H), and a 3389C-T transition in exon 24 that resulted in a thr1130-to-met substitution (T1130M; {603234.0024}). His sister carried the T1130M mutation and a 33-bp deletion ({603234.0023}). The mother, who had PXE also, was deduced to a compound heterozygote for the deletion and T1130M, whereas the father was assumed to be heterozygous for the D1238H mutation which was shared by the sibs; however, DNA was not available for study on either parent. mutations ABCC6, ASP1238HIS number 22 clinvarAccessions RCV000006959;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs387906353 text In the Algerian pedigree studied by {10:Chassaing et al. (2004)}, a female patient with PXE ({264800}) carried a 33-bp deletion in exon 9 of the ABCC6 gene (1088-1120del) in compound heterozygosity with a missense mutation ({603234.0024}). The mutation led to the deletion of 11 amino acids in the transmembrane and intracellular domains (Gln363_Arg373del). mutations ABCC6, 33-BP DEL number 23 clinvarAccessions RCV000006960;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs63750459 text See {603234.0022} and {10:Chassaing et al. (2004)}. The T1130M substitution arose from a 3389C-T transition in exon 24. mutations ABCC6, THR1130MET number 24 clinvarAccessions RCV000006947;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs67561842 text In a 28-year-old French man with pseudoxanthoma elasticum (PXE; {264800}), who had a younger brother who died of generalized arterial calcification of infancy (GACI2; {614473}) at age 15 months, {29:Le Boulanger et al. (2010)} identified compound heterozygosity for missense mutations in the ABCC6 gene: an arg765-to-gln (R765Q) substitution and a gln1406-to-lys (Q1406K; {603234.0026}) substitution. The mutations were found in heterozygosity in each of his unaffected parents, respectively. Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. {29:Le Boulanger et al. (2010)} concluded that GACI may represent an atypical and severe end of the vascular phenotype spectrum of PXE. (The mutations identified by {29:Le Boulanger et al. (2010)} were listed as R765Q and Q1406K in their text, but as E765Q and E1406K in their Figure 3.) The R765Q mutation in exon 18 of the ABCC6 gene has also been identified in heterozygosity and in compound heterozygosity with another ABCC6 mutation in patients with PXE (see {30:Le Saux et al., 2001} and {39:Miksch et al., 2005}, respectively). mutations ABCC6, ARG765GLN number 25 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000023276;;1;;;RCV000023275;;1 status live name PSEUDOXANTHOMA ELASTICUM dbSnps rs387906859 text See {603234.0025} and {29:Le Boulanger et al. (2010)}. mutations ABCC6, GLN1406LYS number 26 alternativeNames ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2, INCLUDED clinvarAccessions RCV000023278;;1;;;RCV000023277;;1 status live name ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2 dbSnps rs72650700 text In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; {614473}), who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, {40:Nitschke et al. (2012)} identified compound heterozygosity for 2 mutations in the ABCC6 gene: an R1141X substitution ({603234.0001}) and a 1552C-T transition in exon 12, resulting in an arg518-to-ter (R518X) substitution. The R518X mutation has also been identified in compound heterozygosity with another ABCC6 mutation in patients with pseudoxanthoma elasticum (PXE; {264800}) (see, e.g., {37:Meloni et al., 2001} and {39:Miksch et al., 2005}). mutations ABCC6, ARG518TER number 27 alternativeNames PSEUDOXANTHOMA ELASTICUM, INCLUDED clinvarAccessions RCV000023280;;1;;;RCV000023279;;1 status live name ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2 dbSnps rs387906860 text See {603234.0006} and {40:Nitschke et al. (2012)}. mutations ABCC6, 1-BP INS, 450C number 28 clinvarAccessions RCV000023281;;1 status moved number 29 name MOVED TO {603234.0002} movedTo 603234.0002 prefix * titles alternativeTitles ANTHRACYCLINE RESISTANCE-ASSOCIATED PROTEIN; ARA;; MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 6; MRP6 preferredTitle ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ABCC6 textSectionList textSection textSectionTitle Description textSectionContent ABCC6 belongs to the multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transmembrane transporters. MRPs are involved in drug resistance, particularly in association with cancer chemotherapy. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE; see {264800}), a heritable connective tissue disorder characterized by calcification of elastic fibers in skin, arteries, and retina ({7:Bergen et al., 2000}; {33:Le Saux et al., 2000}; {47:Ringpfeil et al., 2000}). textSectionName description textSectionTitle Cloning textSectionContent Multidrug resistance in cancer cells has been attributed to the overexpression of certain membrane proteins, several of which are members of the ATP-binding cassette (ABC) superfamily. Examples include MRP ({158343}) and MDR1 ({171050}). {35:Longhurst et al. (1996)} screened an E1000 leukemia cell cDNA library using an MRP probe. They cloned a novel cDNA encoding a 453-amino acid polypeptide that was similar to the C-terminal half of MRP. Whereas MRP contains 2 ABC domains and 12 transmembrane domains, the ARA protein contains 1 ABC domain and 5 transmembrane domains. Northern blot analysis showed that ARA was expressed as a 2.2-kb mRNA in an E1000 leukemia cell line, but not in the untransformed parental CEM cell line. Southern blot analysis revealed that, like MRP, the ARA gene was amplified in the genomic DNA of the E1000 cell line. The ABCC6 protein consists of 1,503 amino acids with a molecular mass of 165 kD, is located in the plasma membrane, and probably has 17 membrane-spanning helices grouped into 3 transmembrane domains ({33:Le Saux et al., 2000}). The 4.5-kb ABCC6 mRNA is expressed in several secretory tissues, but primarily in kidney and liver. By RT-PCR analysis using RNA isolated from tissues frequently affected by PXE, {7:Bergen et al. (2000)} detected expression of ABCC6 in retina, skin, and vascular tissue, although the highest level of expression was in the liver. By Western blot analysis of transfected Chinese hamster ovary (CHO) cells, {4:Belinsky et al. (2002)} found that MRP6 migrated at the predicted molecular mass of about 152 kD and at 182 kD, which likely represents a glycosylated form. {51:Sinko et al. (2003)} found that human ABCC6, when expressed by retroviral transduction in polarized mammalian cells (MDCKII), is exclusively localized to the basolateral membrane. In contrast to the in vitro translated protein, ABCC6 was glycosylated in MDCK cells. Limited proteolysis of the fully glycosylated and underglycosylated forms, followed by immunodetection with region-specific antibodies, indicated that asn15, located in the extracellular N-terminal region of ABCC6, is the only N-glycosylated site in the protein. By in situ hybridization and immunohistochemical analysis, {3:Beck et al. (2005)} detected ABCC6 mRNA and protein in a wide range of epithelial cells of exocrine and endocrine tissues such as acinar cells in the pancreas, mucosal cells of the intestine, and follicular epithelial cells of the thyroid. Enteroendocrine G cells of the stomach showed strong immunostaining. In addition, ABCC6 mRNA and protein were present in most neurons of the brain, in alveolar macrophages in the lung, in lymph node lymphocytes, in hepatocytes, and in keratinocytes and epithelial cells of the ducts of sweat glands. Using PCR, {36:Matsuzaki et al. (2005)} found that Abcc6 expression was highest in mouse liver and lower in kidney and small intestine. Second-round nested PCR revealed much weaker expression in brain, tongue, stomach, and eye. Subcloning and sequencing of distinct PCR products indicated that the 3-prime end is subject to aberrant splicing, resulting in each case in a premature termination codon. PCR analysis of cultured human cells revealed similar splice variations in the 3-prime end resulting in the skipping of exons 24 and 30 in epidermal keratinocytes, and exons 24, 26, and 28 in dermal fibroblasts. In fibroblasts, a minor PCR product represented alternative splicing of exon 7. textSectionName cloning textSectionTitle Gene Structure textSectionContent {27:Kool et al. (1999)} determined that the human ABCC6 gene contains 31 exons. {46:Ratajewski et al. (2008)} found that the 5-prime upstream region of the ABCC6 gene contains a major Alu element of over 4.5 kb. textSectionName geneStructure textSectionTitle Gene Function textSectionContent {5:Belinsky and Kruh (1999)} and {25:Klein et al. (1999)} suggested that ABCC6 function may be related to cellular detoxification rather than drug resistance. {7:Bergen et al. (2000)} commented that the molecules presumably transported by ABCC6 may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. Given the high expression of ABCC6 in liver and kidney, ABCC6 substrates may be transported into the blood. A deficiency of specific ABCC6 substrates may affect a range of connective tissue sites throughout the body and specifically elastic fiber assembly. By assaying membrane vesicles obtained from ABCC6-expressing insect cells, {20:Ilias et al. (2002)} found ABCC6 specifically bound MgATP and actively transported glutathione conjugates, including leukotriene-C4 and N-ethylmaleimide S-glutathione (NEM-GS), in an MgATP-dependent manner. 17-Beta-estradiol-17-beta-D-glucuronide was a weak transport substrate. The organic anions probenecid, benzbromarone, and indomethacin specifically inhibited ABCC6-mediated NEM-GS transport, and orthovanadate, a phosphotyrosine phosphatase inhibitor, completely inhibited NEM-GS transport. Using similar substrates to those used by {20:Ilias et al. (2002)}, {4:Belinsky et al. (2002)} found that MRP6 expressed in CHO cell membranes could transport glutathione conjugates but not glucuronate conjugates. Transfected cells also showed enhanced resistance to several anticancer agents. The highest levels of resistance were observed for the inhibitors of topoisomerase II ({126430}) etoposide and teniposide, followed by the anthracyclines doxorubicin and daunorubicin. MRP6-expressing CHO cells accumulated less etoposide compared with control transfected cells, indicating that MRP6 functions as a drug efflux pump. Using a luciferase reporter gene construct, {23:Jiang et al. (2006)} examined the 2.6-kb human ABCC6 promoter. An NF-kappa-B (see NFKB1, {164011})-like sequence conferred strong expression in HepG2 hepatoma cells, but much weaker expression in cell lines of other tissue origin. Injection of the construct into mouse tail vein confirmed liver-specific expression. Testing of selected cytokines revealed that TGF-beta ({190180}) upregulated, while TNF-alpha ({191160}) and interferon-gamma (IFNG; {147570}) downregulated, the promoter activity in HepG2 cells. The responsiveness to TGF-beta resided primarily within an SP1 ({189906})/SP3 ({601804}) binding site. The expression of the ABCC6 promoter was markedly enhanced by SP1. {23:Jiang et al. (2006)} concluded that the expression of ABCC6 can be modulated by proinflammatory cytokines. Using the ABCC6 promoter region in reporter gene assays in the HepG2 hepatoma cell line, {45:Ratajewski et al. (2006)} showed that all-trans retinoic acid caused significant induction of ABCC6 activity. They found 9-cis retinoic acid (9cRA), a specific RXR (see RXRA, {180245}) receptor agonist, induced the ABCC6 promoter in a concentration-dependent manner. 9cRA also induced the expression of endogenous ABCC6 in HepG2 cells. The binding of RXR to the endogenous ABCC6 promoter was confirmed by chromatin immunoprecipitation experiments. Occupancy of the ABCC6 promoter by RXR was relatively high in unstimulated cells and increased further in 9cRA-treated cells. Using the ABCC6 reporter construct described by {45:Ratajewski et al. (2006)} in a screen for ABCC6-regulating factors, {46:Ratajewski et al. (2008)} found that GATA3 ({131320}) repressed ABCC6 activity, and that SP1, PLAG1 ({603026}), and PLAGL1 ({603044}) induced ABCC6 activity. They identified 2 putative PLAG-binding sites on the reverse strand of the ABCC6 proximal promoter. Reporter gene assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation analysis showed that the more proximal site was bound and activated by PLAG1 and PLAGL1. Furthermore, overexpression of PLAG1 resulted in enhanced ABCC6 transcription in transfected human embryonic kidney cells. textSectionName geneFunction textSectionTitle Mapping textSectionContent {28:Kuss et al. (1998)} used fluorescence in situ hybridization to map the ARA gene to human chromosome 16p13.1. The gene order in this region is telomere--MYH11({160745})--MRP--ARA--centromere. The MRP and ARA genes are located within 9 kb of each other and are transcribed in opposite directions. Both MRP and ARA are deleted in a subgroup of inv(16) leukemias, and both are expressed in normal hematopoietic precursor cells. Pseudogenes {44:Pulkkinen et al. (2001)} identified 2 pseudogenes containing sequences highly homologous to the 5-prime end of the ABCC6 gene. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Pseudoxanthoma Elasticum Simultaneously and independently, {7:Bergen et al. (2000)}, {33:Le Saux et al. (2000)}, and {47:Ringpfeil et al. (2000)} identified missense, nonsense, and splice site mutations as well as deletions and insertions in the ABCC6 gene causing pseudoxanthoma elasticum ({264800}). Mutations appeared to represent autosomal recessive ({33:Le Saux et al., 2000}) and autosomal dominant ({177850}) ({7:Bergen et al., 2000}) modes of inheritance, and sporadic cases. By SSCP and heteroduplex analysis using genetic DNA from a cohort of 17 unrelated PXE patients, {33:Le Saux et al. (2000)} screened 109 exons within 5 PXE candidate genes in the chromosome 16p13.1 region for mutations. By screening the 31 exons of ABCC6 by SSCP, {33:Le Saux et al. (2000)} identified 6 mutations that were responsible for PXE in 10 of 17 patients. They identified a C-to-T substitution within exon 24 at nucleotide 3421, resulting in an arg-to-stop substitution at codon 1141 (R1141X; {603234.0001}) in 6 unrelated families with autosomal recessive PXE. {7:Bergen et al. (2000)} identified mutations in ABCC6 causing autosomal dominant, autosomal recessive, and sporadic PXE. {7:Bergen et al. (2000)} found the R114X mutation in 2 families with autosomal dominant PXE. One patient had a large de novo deletion of chromosome 16 ({603234.0010}). {47:Ringpfeil et al. (2000)} reported a total of 8 pathogenetic mutations in the ABCC6 gene in 8 kindreds with PXE. They referred to the gene as MRP6 (multidrug resistance-associated protein-6). Examination of clinically unaffected family members in 4 multiplex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern. {30:Le Saux et al. (2001)} performed a mutation analysis of the ABCC6 gene in 122 unrelated patients with PXE, the largest cohort of patients studied to that time. They characterized 36 mutations, 28 of which were novel. Twenty-one were missense variants, 6 were small insertions or deletions, 5 were nonsense, 2 were alleles likely to result in aberrant mRNA splicing, and 2 were large deletions involving ABCC6. Although most mutations appeared to be unique variants, 2 disease-causing alleles occurred frequently in apparently unrelated individuals. Arg1141 to ter (R1141X; {603234.0001}) was found in this patient cohort at a frequency of 18.8% and was preponderant in European patients. Deletion of nucleotides 23-29 ({603234.0016}) occurred at a frequency of 12.9% and was prevalent in patients from the United States. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least 1 disease-causing allele. The results suggested that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. A cluster of disease-causing variants was observed within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain. While implementing a strategy to screen for PXE by complete mutation analysis of the ABCC6 gene, {12:Germain (2001)} found evidence for the existence of at least 1 pseudogene highly homologous to the 5-prime end of ABCC6. Sequence variants in this ABCC6-like pseudogene could be mistaken for mutations in the ABCC6 gene and consequently lead to erroneous genotyping results in pedigrees affected with PXE. {13:Germain et al. (2001)} identified a heterozygous missense mutation in exon 7 of the ABCC6 gene in a female PXE patient whose parents were second cousins. Despite complete scanning of the gene, no further mutation was evident. A heterozygous profile was also found in the proband's unaffected children. However, haplotype homozygosity was confirmed at chromosome 16p13.1, using both extragenic microsatellites and intragenic polymorphisms located 3-prime from the mutation, in agreement with the known consanguinity in the family. Taken together, the data indicated that PCR products of exon 7 of the ABCC6 gene were amplified from more than 2 genomic copies. This supported the existence of one or more ABCC6 pseudogenes highly homologous to the 5-prime end (exons 1-9) of the ABCC6 gene. {44:Pulkkinen et al. (2001)} identified 2 pseudogenes containing sequences highly homologous to the 5-prime end of the ABCC6 gene. Nucleotide differences in flanking introns between these 2 pseudogenes and ABCC6 allowed them to design allele-specific primers that eliminated the amplification of both pseudogene sequences by PCR and provided reliable amplification of ABCC6-specific sequences only. The use of allele-specific PCR revealed 2 novel 5-prime-end PXE mutations. In 59 unrelated Dutch patients with PXE, {19:Hu et al. (2003)} identified 17 different mutations, including 11 novel mutations, in the ABCC6 gene in 65 alleles. The R1141X mutation was by far the most common mutation, identified in 19 (32.2%) patients; the second most common mutation, which results in the deletion of exons 23-29 ({603234.0016}), was identified in 11 (18.6%) patients. In 20 patients, only 1 mutation in 1 allele was detected. Combined with previous mutation data, {19:Hu et al. (2003)} concluded that approximately 80% of the PXE mutations occur in the cytoplasmic domains of the predicted ABCC6 protein, especially the 2 nucleotide-binding fold (NBF) domains (NBF1 and NBF2) and the eighth cytoplasmic loop between the fifteenth and sixteenth transmembrane regions. {18:Hu et al. (2004)} described an efficient molecular diagnostic strategy for ABCC6 in PXE. The 2 most frequent mutations, R1141X ({603234.0001}) and deletion of exons 23 through 29 ({603234.0016}), as well as a core set of mutations, were identified by restriction enzyme digestion and size separation on agarose gels. In the remaining patient group in which only 1 or no mutant allele was found, the complete coding sequence was analyzed using DHPLC. All variations found were confirmed by direct DNA sequencing. Finally, Southern blot was used to investigate the potential presence of small or large deletions. Twenty different mutations, including 2 novel mutations in the ABCC6 gene, were identified in 80.3% of the 76 patients, and 58.6% of the 152 ABCC6 alleles analyzed. {9:Chassaing et al. (2005)} commented that mutations had been identified in PXE in most of the 31 ABCC6 exons and that no correlation between the nature or the location of the mutations and phenotype severity had been established. {53:Trip et al. (2002)}, {54:Van Soest et al. (1997)}, and {2:Bacchelli et al. (1999)} emphasized the carriage of a sole ABCC6 mutation as a cardiovascular risk factor. {50:Sherer et al. (2001)} described limited phenotypic expression of PXE in parents of affected offspring. {39:Miksch et al. (2005)} performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. Their mutational analysis confirmed an earlier haplotype-based analysis and conclusions regarding a recessive-only mode of inheritance in PXE ({8:Cai et al., 2000}) through the identification of 2 mutated alleles in all individuals with PXE who appear in either consecutive or alternating generations of the same family. Their study demonstrated that the full phenotypic expression of the disorder requires 2 defective allelic copies of ABCC6 and that pseudodominance is the mode of transmission in presumed autosomal dominant families (i.e., the second parental disease allele 'marries into' the family). The apparent frequency of this mechanism was approximately 7.5% in their family cohort. {39:Miksch et al. (2005)} stated that in their families no heterozygote for a large deletion showed any apparent clinical sign of PXE according to category I diagnostic criteria. {9:Chassaing et al. (2005)} provided a comprehensive catalog of ABCC6 mutations identified in PXE. {41:Pfendner et al. (2007)} collected mutation data on an international case series of 270 patients with PXE (239 probands, 31 affected family members). In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations clustered in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X ({603234.0001}) and del23-29 ({603234.0016}) mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the type of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, {11:Costrop et al. (2010)} identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE. Generalized Arterial Calcification of Infancy 2 In a 28-year-old French man with PXE, who had a younger brother who died of generalized arterial calcification of infancy (GACI1; {614473}) at age 15 months, {29:Le Boulanger et al. (2010)} identified compound heterozygosity for missense mutations in the ABCC6 gene ({603234.0025} and {603234.0026}), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the known GACI1 ({208000})-related gene, ENPP1 ({173335}). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. {29:Le Boulanger et al. (2010)} concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE. {40:Nitschke et al. (2012)} analyzed the ABCC6 gene in 28 GACI patients from 25 unrelated families who were negative for mutation in the ENNP1 gene, as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had been detected. They identified homozygosity or compound heterozygosity for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g., {603234.0001}, {603234.0002}, {603234.0006}, and {603234.0027}-{603234.0028}). In 6 patients from 5 unrelated families, only 1 mutation was detected in ABCC6; the authors noted that there was no phenotypic difference between these patients and those with biallelic mutations in ABCC6, and stated that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their approach. No mutation in the ABCC6 gene was found in 16 patients from 14 unrelated families, including the 2 patients who were known to carry monoallelic mutations in ENNP1. Overall, 13 different ABCC6 mutations were identified in GACI patients, all but 2 of which had been previously identified in typical PXE patients who had a much milder phenotype than the GACI patients. Based on the considerable overlap of phenotype and genotype of GACI and pseudoxanthoma elasticum, {40:Nitschke et al. (2012)} suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders. textSectionName molecularGenetics textSectionTitle Population Genetics textSectionContent The Afrikaner population of South Africa is of Dutch, German, and French Huguenot descent and has its origin in the first European immigrant settlements at the Cape of Good Hope during the 17th century. {52:Torrington and Viljoen (1991)} proposed that the basis for the high prevalence of PXE in the Afrikaner population is a founder effect. An initial genealogic study traced the ancestry of 20 Afrikaner families with PXE back to potentially only 4 individuals, suggesting that this disorder is most likely derived from these original founders in South Africa. To study this possibility further, {31:Le Saux et al. (2002)} performed haplotype and mutation analyses in 17 of the 20 originally analyzed Afrikaner families, and identified 3 common haplotypes and 6 different disease-causing variants. Three of these mutant alleles were missense variants, 2 were nonsense mutations, and 1 was a single-basepair insertion. The most common variant, arg1339 to cys (R1339C; {603234.0017}), accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3 to 12%. Haplotype analysis of the Afrikaner families showed that the 3 most frequent mutations were identical by descent, indicating a founder origin of PXE in this population. {9:Chassaing et al. (2005)} suggested that the proposed prevalence of PXE of 1 in 25,000 may be an underestimation. Consequently, the prevalence of heterozygous carriers, and the prevalence of different organ involvement in carriers of 1 or 2 ABCC6 mutations, are not precisely known. textSectionName populationGenetics textSectionTitle Pathogenesis textSectionContent Since the ABCC6 gene is expressed primarily, if not exclusively, in the liver and kidneys, {49:Ringpfeil et al. (2001)} suggested that PXE is a primary metabolic disorder with secondary involvement of elastic fibers, a situation comparable to the secondary involvement of connective tissue elements in homocystinuria ({236200}) and alkaptonuria ({203500}). ABCC6 is a member of the large ATP-dependent transmembrane transporter family. {9:Chassaing et al. (2005)} commented that the association of PXE to ABCC6 efflux transport alterations raised a number of pathophysiology hypotheses, among them, the idea that PXE is a systemic metabolic disease resulting from lack or accumulation over time in the bloodstream of molecules interacting with the synthesis, turnover, and/or maintenance of extracellular matrix (ECM). Since ABCC6 is expressed primarily in the liver, {24:Jiang and Uitto (2006)} likewise supported the notion that PXE is a metabolic disease. In an investigation of the functional relationship between ABCC6 deficiency and elastic fiber calcification, {32:Le Saux et al. (2006)} speculated that ABCC6 deficiency in PXE patients induces a persistent imbalance in circulating metabolite(s) which impairs the synthetic abilities of normal elastoblasts or specifically alters elastic fiber assembly. They found that PXE fibroblasts cultured with normal human serum expressed and deposited increased amounts of proteins, but structurally normal elastic fibers. Normal and PXE fibroblasts as well as normal smooth muscle cells deposited abnormal aggregates of elastic fibers when maintained in the presence of serum from PXE patients. The expression of tropoelastin (see {130160}) and other elastic fiber-associated genes was not significantly modulated by the presence of PXE serum. These results indicated that certain metabolites present in PXE sera interfered with the normal assembly of elastic fibers in vitro and suggested that PXE is a primary metabolic disorder with secondary connective tissue manifestations. textSectionName pathogenesis textSectionTitle Animal Model textSectionContent To elucidate the pathogenesis of PXE, {26:Klement et al. (2005)} generated a transgenic mouse by targeted ablation of the mouse Abcc6 gene. Abcc6-null mice were negative for expression of Mrp6 in the liver, and necropsies revealed profound mineralization of several tissues including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wildtype mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6 -/- mice but was not observed in heterozygous or wildtype mice up to 2 years of age. Total body computerized tomography scan of Abcc6 -/- mice showed mineralization in skin and subcutaneous tissue as well as in kidneys. These data demonstrated aberrant mineralization of soft tissues in PXE-affected organs, and consequently, these mice recapitulated features of this complex disease. {16:Gorgels et al. (2005)} generated Abcc6 -/- mice and showed by light and electron microscopy that Abcc6 -/- mice spontaneously developed calcification of elastic fibers in blood vessel walls and in Bruch membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6 -/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. {16:Gorgels et al. (2005)} concluded that the phenotype of the Abcc6 -/- mouse shares calcification of elastic fibers with human PXE pathology, and supports the hypothesis that PXE is a systemic disease. To characterize the mineralization process in PXE, {22:Jiang et al. (2007)} examined a PXE animal model, the Abcc6 -/- mouse, with respect to specific proteins serving as inhibitors of mineralization. The levels of calcium and phosphate in serum of these mice were normal, but the Abcc6 -/- serum had less ability to prevent the mineral deposition induced by inorganic phosphate in a cell culture system. Addition of fetuin-A ({138680}) to the culture system prevented the mineralization. The calcium-phosphate product was markedly elevated in the mineralized vibrissae of Abcc6 -/- mice, an early biomarker of the mineralization process, consistent with histopathologic findings. Levels of fetuin-A were slightly decreased in Abcc6 -/- serum, and positive immunostaining for matrix-Gla-protein (MGP; {154870}), fetuin-A, and ankylosis protein (ANK; {605145}) as well as alkaline phosphatase activity were strongly associated with the mineralization process. In situ hybridization demonstrated that the genes for MGP and Ank were expressed locally in vibrissae, whereas fetuin-A was expressed highly in the liver. These data suggested that the deposition of the bone-associated proteins spatially coincides with mineralization and actively regulates this process locally and systemically. In the Dyscalc1 mouse model of dystrophic cardiac calcification (DCC), {38:Meng et al. (2007)} studied 2 intercrosses and identified Abcc6 as the causative gene, which was confirmed by transgenic complementation. The authors noted that myocardial calcification has not been reported as a phenotype associated with human PXE or mouse Abcc6-knockout models. In all mouse strains positive for DCC, {1:Aherrahrou et al. (2008)} identified a missense mutation at the 3-prime border of exon 14 of the Abcc6 gene that created an additional donor splice site. The alternative transcript lacked the last 5 nucleotides of exon 14, resulting in premature termination at codon 684, and leading to Abcc6 protein deficiency in DCC-susceptible mice. {21:Jiang et al. (2009)} found that grafting of wildtype mouse muzzle skin onto the back of Abcc6-knockout mice resulted in abnormal mineralization of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout mouse muzzle skin onto wildtype mice did not. The data implied that PXE does not result from localized defect based on resident cellular abnormalities but from a change of metabolite(s) in serum. These findings implicate circulatory factors as a critical component of the mineralization process and supported the notion that PXE is a secondary mineralization of connective tissues. In addition, the findings suggested that the abnormal mineralization process could possibly be countered or even reversed by changes in the homeostatic milieu. textSectionName animalModel geneMapExists true editHistory carol : 02/26/2014 carol : 10/1/2013 alopez : 7/18/2012 carol : 2/8/2012 terry : 2/8/2012 carol : 2/8/2012 alopez : 6/29/2010 terry : 6/18/2010 wwang : 6/18/2010 ckniffin : 3/25/2010 ckniffin : 11/3/2009 wwang : 10/30/2009 ckniffin : 10/14/2009 alopez : 5/13/2009 mgross : 1/8/2009 terry : 1/6/2009 wwang : 10/28/2008 wwang : 8/5/2008 wwang : 8/5/2008 alopez : 1/24/2008 terry : 12/28/2007 wwang : 10/3/2007 wwang : 4/30/2007 alopez : 3/13/2007 alopez : 3/9/2007 alopez : 3/9/2007 terry : 3/6/2007 alopez : 2/28/2007 alopez : 2/28/2007 alopez : 2/28/2007 mgross : 11/29/2006 joanna : 12/20/2005 alopez : 10/12/2005 alopez : 9/21/2005 carol : 4/9/2004 ckniffin : 4/1/2004 ckniffin : 10/17/2003 carol : 8/22/2003 carol : 3/18/2003 tkritzer : 3/13/2003 terry : 3/10/2003 tkritzer : 11/22/2002 tkritzer : 11/15/2002 terry : 11/13/2002 carol : 8/9/2002 carol : 7/31/2002 carol : 1/3/2002 carol : 11/21/2001 mcapotos : 10/30/2001 mcapotos : 10/30/2001 mcapotos : 10/25/2001 terry : 10/17/2001 cwells : 3/29/2001 terry : 3/19/2001 mcapotos : 9/5/2000 carol : 6/14/2000 carol : 6/1/2000 carol : 6/1/2000 carol : 5/30/2000 alopez : 5/22/2000 alopez : 5/22/2000 carol : 11/9/1999 alopez : 12/2/1998 alopez : 10/29/1998 dateCreated Thu, 29 Oct 1998 03:00:00 EST creationDate Jennifer P. Macke : 10/29/1998 epochUpdated 1393401600 dateUpdated Wed, 26 Feb 2014 03:00:00 EST referenceList reference articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18201967 publisherName HighWire Press title An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H/He mice. mimNumber 603234 referenceNumber 1 publisherAbbreviation HighWire pubmedID 18201967 source J. Biol. Chem. 283: 7608-7615, 2008. authors Aherrahrou, Z., Doehring, D. C., Ehlers, E.-M., Liptau, H., Depping, R., Linsel-Nitschke, P., Kaczmarek, P. M., Erdmann, J., Schunkert, H. pubmedImages false publisherUrl http://highwire.stanford.edu title Identification of heterozygote carriers in families with a recessive form of pseudoxanthoma elasticum (PXE). mimNumber 603234 referenceNumber 2 pubmedID 10619263 source Mod. Pathol. 12: 1112-1123, 1999. authors Bacchelli, B., Quaglino, D., Gheduzzi, D., Taparelli, F., Boraldi, F., Trolli, B., Le Saux, O., Boyd, C. D., Ronchetti, I. P. pubmedImages false articleUrl http://dx.doi.org/10.1007/s00418-004-0744-3 publisherName Springer title Analysis of ABCC6 (MRP6) in normal human tissues. mimNumber 603234 referenceNumber 3 publisherAbbreviation Springer pubmedID 15889270 source Histochem. Cell Biol. 123: 517-528, 2005. authors Beck, K., Hayashi, K., Dang, K., Hayashi, M., Boyd, C. D. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12414644 publisherName HighWire Press title Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). mimNumber 603234 referenceNumber 4 publisherAbbreviation HighWire pubmedID 12414644 source Cancer Res. 62: 6172-6177, 2002. authors Belinsky, M. G., Chen, Z.-S., Shchaveleva, I., Zeng, H., Kruh, G. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.bjc.6690527 publisherName Nature Publishing Group title MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver. mimNumber 603234 referenceNumber 5 publisherAbbreviation NPG pubmedID 10424734 source Brit. J. Cancer 80: 1342-1349, 1999. authors Belinsky, M. G., Kruh, G. D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.jid.5700129 publisherName Nature Publishing Group title Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. (Commentary) mimNumber 603234 referenceNumber 6 publisherAbbreviation NPG pubmedID 16541094 source J. Invest. Derm. 126: 704-705, 2006. authors Bergen, A. A. B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/76109 publisherName Nature Publishing Group title Mutations in ABCC6 cause pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 7 publisherAbbreviation NPG pubmedID 10835643 source Nature Genet. 25: 228-231, 2000. authors Bergen, A. A. B., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., de Jong, P. T. V. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://link.springer.de/link/service/journals/00109/bibs/0078001/00780036.htm publisherName Springer title A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high resolution mapping and genomic structure. mimNumber 603234 referenceNumber 8 publisherAbbreviation Springer pubmedID 10759028 source J. Molec. Med. 78: 36-46, 2000. authors Cai, L., Struk, B., Adams, M. D., Ji, W., Haaf, T., Kang, H.-L., Dho, S. H., Xu, X., Ringpfeil, F., Nancarrow, J., Zach, S., Schaen, L., {and 19 others} pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15894595 publisherName HighWire Press title Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. mimNumber 603234 referenceNumber 9 publisherAbbreviation HighWire pubmedID 15894595 source J. Med. Genet. 42: 881-892, 2005. authors Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1111/j.0022-202X.2004.22312.x publisherName Nature Publishing Group title Novel ABCC6 mutations in pseudoxanthomas elasticum. mimNumber 603234 referenceNumber 10 publisherAbbreviation NPG pubmedID 15086542 source J. Invest. Derm. 122: 608-613, 2004. authors Chassaing, N., Martin, L., Mazereeuw, J., Barrie, L., Nizard, S., Bonafe, J.-L., Calvas, P., Hovnanian, A. pubmedImages false publisherUrl http://www.nature.com title Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region. mimNumber 603234 referenceNumber 11 pubmedID 20075945 source J. Hum. Genet. 55: 112-117, 2010. authors Costrop, L. M. F., Vanakker, O. O. M., Van Laer, L., Le Saux, O., Martin, L., Chassaing, N., Guerra, D., Pasquali-Ronchetti, I., Coucke, P. J., De Paepe, A. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=11474653 publisherName HighWire Press title Pseudoxanthoma elasticum: evidence for the existence of a pseudogene highly homologous to the ABCC6 gene. (Letter) mimNumber 603234 referenceNumber 12 publisherAbbreviation HighWire pubmedID 11474653 source J. Med. Genet. 38: 457-460, 2001. authors Germain, D. P. pubmedImages false publisherUrl http://highwire.stanford.edu source Gene Funct. Dis. 2: 208-213, 2001. mimNumber 603234 authors Germain, D. P., Nau, V., Esnault, C., Jeunemaitre, X., Bruneval, P. title Pseudoxanthoma elasticum: molecular investigations in a consanguineous family further supports the existence of pseudogenes (psi-ABCC6) homologous to the ABCC6 gene. referenceNumber 13 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(00)93101-2 publisherName Elsevier Science title Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing. mimNumber 603234 referenceNumber 14 publisherAbbreviation ES pubmedID 10913334 source Biochem. Biophys. Res. Commun. 274: 297-301, 2000. authors Germain, D. P., Perdu, J., Remones, V., Jeunemaitre, X. pubmedImages false publisherUrl http://www.elsevier.com/ source Pediat. Transplant. 10: 225-233, 2006. mimNumber 603234 authors Glatz, A. C., Pawel, B. R., Hsu, D. T., Weinberg, P., Chrisant, M. R. K. title Idiopathic infantile arterial calcification: two case reports, a review of the literature and a role for cardiac transplantation. referenceNumber 15 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15888484 publisherName HighWire Press title Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 16 publisherAbbreviation HighWire pubmedID 15888484 source Hum. Molec. Genet. 14: 1763-1773, 2005. authors Gorgels, T. G. M. F., Hu, X., Scheffer, G. L., van der Wal, A. C., Toonstra, J., de Jong, P. T. V. M., van Kuppevelt, T. H., Levelt, C. N., de Wolf, A., Loves, W. J. P., Scheper, R. J., Peek, R., Bergen, A. A. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.iovs.org/cgi/pmidlookup?view=long&pmid=12714611 publisherName HighWire Press title Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 17 publisherAbbreviation HighWire pubmedID 12714611 source Invest. Ophthal. Vis. Sci. 44: 1824-1829, 2003. authors Hu, X., Peek, R., Plomp, A., ten Brink, J., Scheffer, G., van Soest, S., Leys, A., de Jong, P. T. V. M., Bergen, A. A. B. pubmedImages false publisherUrl http://highwire.stanford.edu title Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 18 pubmedID 15727254 source Genet. Test. 8: 292-300, 2004. authors Hu, X., Plomp, A., Gorgels, T., Ten Brink, J., Loves, W., Mannens, M., De Jong, P. T. V. M., Bergen, A. A. B. pubmedImages false articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200953 publisherName Nature Publishing Group title ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 19 publisherAbbreviation NPG pubmedID 12673275 source Europ. J. Hum. Genet. 11: 215-224, 2003. authors Hu, X., Plomp, A., Wijnholds, J., ten Brink, J., van Soest, S., van den Born, L. I., Leys, A., Peek, R., de Jong, P. T. V. M., Bergen, A. A. B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11880368 publisherName HighWire Press title Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). mimNumber 603234 referenceNumber 20 publisherAbbreviation HighWire pubmedID 11880368 source J. Biol. Chem. 277: 16860-16867, 2002. Note: Erratum: J. Biol. Chem. 277: 24842 only, 2002. authors Ilias, A., Urban, Z., Seidl, T. L., Le Saux, O., Sinko, E., Boyd, C. D., Sarkadi, B., Varadi, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/jid.2008.212 publisherName Nature Publishing Group title Pseudoxanthoma elasticum is a metabolic disease. mimNumber 603234 referenceNumber 21 publisherAbbreviation NPG pubmedID 18685618 source J. Invest. Derm. 129: 348-354, 2009. authors Jiang, Q., Endo, M., Dibra, F., Wang, K., Uitto, J. pubmedImages true publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.jid.5700729 publisherName Nature Publishing Group title Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors. mimNumber 603234 referenceNumber 22 publisherAbbreviation NPG pubmedID 17273159 source J. Invest. Derm. 127: 1392-1402, 2007. authors Jiang, Q., Li, Q., Uitto, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.jid.5700065 publisherName Nature Publishing Group title Transcriptional regulation and characterization of the promoter region of the human ABCC6 gene. mimNumber 603234 referenceNumber 23 publisherAbbreviation NPG pubmedID 16374464 source J. Invest. Derm. 126: 325-355, 2006. authors Jiang, Q., Matsuzaki, Y., Li, K., Uitto, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.jid.5700267 publisherName Nature Publishing Group title Pseudoxanthoma elasticum: a metabolic disease? (Commentary) mimNumber 603234 referenceNumber 24 publisherAbbreviation NPG pubmedID 16778810 source J. Invest. Derm. 126: 1440-1441, 2006. authors Jiang, Q., Uitto, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0005-2736(99)00161-3 publisherName Elsevier Science title An inventory of the human ABC proteins. mimNumber 603234 referenceNumber 25 publisherAbbreviation ES pubmedID 10581359 source Biochim. Biophys. Acta 1461: 237-262, 1999. authors Klein, I., Sarkadi, B., Varadi, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=16135817 publisherName HighWire Press title Targeted ablation of the Abcc6 gene results in ectopic mineralization of connective tissues. mimNumber 603234 referenceNumber 26 publisherAbbreviation HighWire pubmedID 16135817 source Molec. Cell. Biol. 25: 8299-8310, 2005. authors Klement, J. F., Matsuzaki, Y., Jiang, Q.-J., Terlizzi, J., Choi, H. Y., Fujimoto, N., Li, K., Pulkkinen, L., Birk, D. E., Sundberg, J. P., Uitto, J. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9892204 publisherName HighWire Press title Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. mimNumber 603234 referenceNumber 27 publisherAbbreviation HighWire pubmedID 9892204 source Cancer Res. 59: 175-182, 1999. authors Kool, M., van der Linden, M., de Haas, M., Baas, F., Borst, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(98)95349-6 publisherName Elsevier Science title ARA, a novel ABC transporter, is located at 16p13.1, is deleted in inv(16) leukemias, and is shown to be expressed in primitive hematopoietic precursors. mimNumber 603234 referenceNumber 28 publisherAbbreviation ES pubmedID 9721217 source Genomics 51: 455-458, 1998. authors Kuss, B. J., O'Neill, G. M., Eyre, H., Doggett, N. A., Callen, D. F., Davey, R. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.33162 publisherName John Wiley & Sons, Inc. title An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy. mimNumber 603234 referenceNumber 29 publisherAbbreviation Wiley pubmedID 20034067 source Am. J. Med. Genet. 152A: 118-123, 2010. authors Le Boulanger, G., Labreze, C., Croue, A., Schurgers, L. J., Chassaing, N., Wittkampf, T., Rutsch, F., Martin, L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61131-8 publisherName Elsevier Science title A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 30 publisherAbbreviation ES pubmedID 11536079 source Am. J. Hum. Genet. 69: 749-764, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1413 only, 2001; Erratum: Am. J. Hum. Genet. 71: 448 only, 2002. authors Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Goring, H. H. H., Johnson, E. W., De Paepe, A., Pope, F. M., Pasquali-Ronchetti, I., Bercovitch, L., Marais, A.-S., Viljoen, D. L., Terry, S. F., Boyd, C. D. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s00439-002-0808-1 publisherName Springer title Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa. mimNumber 603234 referenceNumber 31 publisherAbbreviation Springer pubmedID 12384774 source Hum. Genet. 111: 331-338, 2002. authors Le Saux, O., Beck, K., Sachsinger, C., Treiber, C., Goring, H. H. H., Curry, K., Johnson, E. W., Bercovitch, L., Marais, A.-S., Terry, S. F., Viljoen, D. L., Boyd, C. D. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1038/sj.jid.5700201 publisherName Nature Publishing Group title Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro. mimNumber 603234 referenceNumber 32 publisherAbbreviation NPG pubmedID 16543900 source J. Invest. Derm. 126: 1497-1505, 2006. authors Le Saux, O., Bunda, S., VanWart, C. M., Douet, V., Got, L., Martin, L., Hinek, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/76102 publisherName Nature Publishing Group title Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 33 publisherAbbreviation NPG pubmedID 10835642 source Nature Genet. 25: 223-227, 2000. authors Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., Boyd, C. D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/jid.2008.271 publisherName Nature Publishing Group title Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes. mimNumber 603234 referenceNumber 34 publisherAbbreviation NPG pubmedID 18800149 source J. Invest. Derm. 129: 553-563, 2009. authors Li, Q., Grange, D. K., Armstrong, N. L., Whelan, A. J., Hurley, M. Y., Rishavy, M. A., Hallgren, K. W., Berkner, K. L., Schurgers, L. J., Jiang, Q., Uitto, J. pubmedImages true publisherUrl http://www.nature.com title The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. mimNumber 603234 referenceNumber 35 pubmedID 8912525 source Brit. J. Cancer 74: 1331-1335, 1996. authors Longhurst, T. J., O'Neill, G. M., Harvie, R. M., Davey, R. A. pubmedImages false articleUrl http://dx.doi.org/10.1111/j.0022-202X.2005.23897.x publisherName Nature Publishing Group title Tissue-specific expression of the ABCC6 gene. mimNumber 603234 referenceNumber 36 publisherAbbreviation NPG pubmedID 16297187 source J. Invest. Derm. 125: 900-905, 2005. authors Matsuzaki, Y., Nakano, A., Jiang, Q.-J., Pulkkinen, L., Uitto, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/humu.1157 publisherName John Wiley & Sons, Inc. title Pseudoxanthoma elasticum: point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11. (Abstract) mimNumber 603234 referenceNumber 37 publisherAbbreviation Wiley pubmedID 11439001 source Hum. Mutat. 18: 85 only, 2001. Note: Full article online. authors Meloni, I., Rubegni, P., De Aloe, G., Bruttini, M., Pianigiani, E., Cusano, R., Seri, M., Mondillo, S., Federico, A., Bardelli, A. M., Andreassi, L., Fimiani, M., Renieri, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17360558 publisherName HighWire Press title Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics. mimNumber 603234 referenceNumber 38 publisherAbbreviation HighWire pubmedID 17360558 source Proc. Nat. Acad. Sci. 104: 4530-4535, 2007. authors Meng, H., Vera, I., Che, N., Wang, X., Wang, S. S., Ingram-Drake, L., Schadt, E. E., Drake, T. A., Lusis, A. J. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.20206 publisherName John Wiley & Sons, Inc. title Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. mimNumber 603234 referenceNumber 39 publisherAbbreviation Wiley pubmedID 16086317 source Hum. Mutat. 26: 235-248, 2005. authors Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(11)00498-8 publisherName Elsevier Science title Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. mimNumber 603234 referenceNumber 40 publisherAbbreviation ES pubmedID 22209248 source Am. J. Hum. Genet. 90: 25-39, 2012. authors Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J., Le Merrer, M., Guest, G., Lambot, K., Tazarourte-Pinturier, M.-F., Chassaing, N., Roche, O., {and 19 others} pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=17617515 publisherName HighWire Press title Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 41 publisherAbbreviation HighWire pubmedID 17617515 source J. Med. Genet. 44: 621-628, 2007. authors Pfendner, E. G., Vanakker, O. M., Terry, S. F., Vourthis, S., McAndrew, P. E., McClain, M. R., Fratta, S., Marais, A.-S., Hariri, S., Coucke, P. J., Ramsay, M., Viljoen, D., Terry, P. F., De Paepe, A., Uitto, J., Bercovitch, L. G. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1098-3600&volume=11&issue=12&spage=852 publisherName Lippincott Williams & Wilkins title Pseudoxanthoma elasticum: wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6. mimNumber 603234 referenceNumber 42 publisherAbbreviation LWW pubmedID 19904211 source Genet. Med. 11: 852-858, 2009. authors Plomp, A. S., Bergen, A. A. B., Florijn, R. J., Terry, S. F., Toonstra, J., van Dijk, M. R., de Jong, P. T. V. M. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.20632 publisherName John Wiley & Sons, Inc. title Does autosomal dominant pseudoxanthoma elasticum exist? mimNumber 603234 referenceNumber 43 publisherAbbreviation Wiley pubmedID 15098239 source Am. J. Med. Genet. 126A: 403-412, 2004. authors Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://link.springer.de/link/service/journals/00439/bibs/1109003/11090356.htm publisherName Springer title Identification of ABCC6 pseudogenes on human chromosome 16p: implications for mutation detection in pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 44 publisherAbbreviation Springer pubmedID 11702217 source Hum. Genet. 109: 356-365, 2001. authors Pulkkinen, L., Nakano, A., Ringpfeil, F., Uitto, J. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(06)02234-0 publisherName Elsevier Science title Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor. mimNumber 603234 referenceNumber 45 publisherAbbreviation ES pubmedID 17045963 source Biochem. Biophys. Res. Commun. 350: 1082-1087, 2006. authors Ratajewski, M., Bartosz, G., Pulaski, L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s00439-008-0570-0 publisherName Springer title The human pseudoxanthoma elasticum gene ABCC6 is transcriptionally regulated by PLAG family transcription factors. mimNumber 603234 referenceNumber 46 publisherAbbreviation Springer pubmedID 18850323 source Hum. Genet. 124: 451-463, 2008. authors Ratajewski, M., Van de Ven, W. J. M., Bartosz, G., Pulaski, L. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10811882 publisherName HighWire Press title Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. mimNumber 603234 referenceNumber 47 publisherAbbreviation HighWire pubmedID 10811882 source Proc. Nat. Acad. Sci. 97: 6001-6006, 2000. authors Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63104-8 publisherName Elsevier Science title Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 48 publisherAbbreviation ES pubmedID 11179012 source Am. J. Hum. Genet. 68: 642-652, 2001. authors Ringpfeil, F., Nakano, A., Uitto, J., Pulkkinen, L. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0906-6705&date=2001&volume=10&issue=4&spage=221 publisherName Blackwell Publishing title Molecular genetics of pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 49 publisherAbbreviation Blackwell pubmedID 11493310 source Exp. Derm. 10: 221-228, 2001. authors Ringpfeil, F., Pulkkinen, L., Uitto, J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0190-9622(01)18896-1 publisherName Elsevier Science title Pseudoxanthoma elasticum: significance of limited phenotypic expression in parents of affected offspring. mimNumber 603234 referenceNumber 50 publisherAbbreviation ES pubmedID 11209132 source J. Am. Acad. Derm. 44: 534-537, 2001. authors Sherer, D. W., Bercovitch, L., Lebwohl, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X03013494 publisherName Elsevier Science title Subcellular localization and N-glycosylation of human ABCC6, expressed in MDCKII cells. mimNumber 603234 referenceNumber 51 publisherAbbreviation ES pubmedID 12901863 source Biochem. Biophys. Res. Commun. 308: 263-269, 2003. authors Sinko, E., Ilias, A., Ujhelly, O., Homolya, L., Scheffer, G. L., Bergen, A. A. B., Sarkadi, B., Varadi, A. pubmedImages false publisherUrl http://www.elsevier.com/ title Founder effect in 20 Afrikaner kindreds with pseudoxanthoma elasticum. mimNumber 603234 referenceNumber 52 pubmedID 1986458 source S. Afr. Med. J. 79: 7-11, 1991. authors Torrington, M., Viljoen, D. L. pubmedImages false articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12176944 publisherName HighWire Press title Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. mimNumber 603234 referenceNumber 53 publisherAbbreviation HighWire pubmedID 12176944 source Circulation 106: 773-775, 2002. authors Trip, M. D., Smulders, Y. M., Wegman, J. J., Hu, X., Boer, J. M., ten Brink, J. B., Zwinderman, A. H., Kastelein, J. J., Feskens, E. J., Bergen, A. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.genome.org/cgi/pmidlookup?view=long&pmid=9267806 publisherName HighWire Press title A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. mimNumber 603234 referenceNumber 54 publisherAbbreviation HighWire pubmedID 9267806 source Genome Res. 7: 830-834, 1997. authors van Soest, S., Swart, J., Tijmes, N., Sandkuijl, L. A., Rommers, J., Bergen, A. A. B. pubmedImages true publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 04453 nbkIDs NBK1113;;Pseudoxanthoma Elasticum refSeqAccessionIDs NG_007558.2 uniGenes Hs.442182 approvedGeneSymbols ABCC6 nextGxDx true locusSpecificDBs http://www.retina-international.org/files/sci-news/abcc6mut.htm;;Mutations of the Multidrug Resistance-associated Protein 6 (ABCC6/ MPR6/ MOAT-E);;;http://www.ncbi.nlm.nih.gov/lovd/home.php?select_db=ABCC6;;LOVD at NCBI dermAtlas false umlsIDs C1412081 gtr true geneIDs 368 swissProtIDs O95255 zfinIDs ZDB-GENE-050517-18,ZDB-GENE-050517-19,ZDB-GENE-110208-2 ensemblIDs ENSG00000091262,ENST00000575728 geneTests true mgiIDs MGI:1351634 ncbiReferenceSequences 530408041,530408040,530408043,190343022,190343012 genbankNucleotideSequences 1871197,147970134,29029245,5764414,3928848,145993119,194390073,124297752,160332572,19221233,383215009,30048189,158147733,148143240,3401103,148143241,148143242,71514172 proteinSequences 119574336,119574337,578840006,5764415,578840008,3928849,578840010,194390074,269849624,124297753,160332573,30048190,3108185,19221234,190343023,118582251,158147734,119574335 geneticsHomeReferenceIDs gene;;ABCC6;;ABCC6

entryList

entry status live allelicVariantExists true epochCreated 897375600 geneMap geneSymbols EP300, RSTS2 sequenceID 14266 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 602700 phenotypeInheritance Autosomal dominant phenotype Colorectal cancer, somatic phenotypeMimNumber 114500 phenotypeMimNumber 613684 mimNumber 602700 phenotypeInheritance Isolated cases; Autosomal dominant phenotypicSeriesMimNumber 180849 phenotypeMappingKey 3 phenotype Rubinstein-Taybi syndrome 2 chromosomeLocationStart 41488613 chromosomeSort 278 chromosomeSymbol 22 mimNumber 602700 geneInheritance None confidence P mappingMethod A geneName E1A-binding protein, 300kD mouseMgiID MGI:1276116 mouseGeneSymbol Ep300 computedCytoLocation 22q13.2 cytoLocation 22q13 transcript uc003azl.4 chromosomeLocationEnd 41576080 chromosome 22 contributors Ada Hamosh - updated : 2/3/2014 Ada Hamosh - updated : 2/7/2013 Ada Hamosh - updated : 3/7/2012 Ada Hamosh - updated : 8/30/2011 Ada Hamosh - updated : 6/14/2011 Ada Hamosh - updated : 6/6/2011 Cassandra L. Kniffin - updated : 1/6/2011 Ada Hamosh - updated : 4/22/2010 Matthew B. Gross - updated : 3/8/2010 Patricia A. Hartz - updated : 12/8/2009 Marla J. F. O'Neill - updated : 10/30/2009 Ada Hamosh - updated : 9/9/2009 Ada Hamosh - updated : 5/19/2009 Ada Hamosh - updated : 3/9/2009 Ada Hamosh - updated : 11/26/2008 Ada Hamosh - updated : 3/20/2008 Cassandra L. Kniffin - updated : 8/13/2007 Ada Hamosh - updated : 1/30/2006 Victor A. McKusick - updated : 3/11/2005 Patricia A. Hartz - updated : 2/23/2005 Stylianos E. Antonarakis - updated : 8/5/2004 Ada Hamosh - updated : 4/22/2003 Ada Hamosh - updated : 2/21/2003 Ada Hamosh -updated : 11/12/2002 Stylianos E. Antonarakis - updated : 9/23/2002 Stylianos E. Antonarakis - updated : 11/5/2001 Stylianos E. Antonarakis - updated : 7/3/2001 Ada Hamosh - updated : 3/12/2001 Victor A. McKusick - updated : 3/1/2000 Patti M. Sherman - updated : 4/16/1999 Ada Hamosh - updated : 4/15/1999 clinicalSynopsisExists false mimNumber 602700 allelicVariantList allelicVariant status live name COLORECTAL CANCER, SOMATIC dbSnps rs137853038 text In 1 of 20 primary colorectal cancers ({114500}), {10:Gayther et al. (2000)} found a somatic arg580-to-ter (R580X) nonsense mutation in the EP300 gene resulting from a C-to-T transition at nucleotide 2837. This was associated with loss of heterozygosity (LOH). mutations EP300, ARG580TER number 1 clinvarAccessions RCV000007283;;1 status live name COLORECTAL CANCER, SOMATIC dbSnps rs28937578 text In a primary colorectal cancer ({114500}), {10:Gayther et al. (2000)} found a somatic 7861C-A transversion in exon 31 of the EP300 gene, resulting in a pro2221-to-gln amino acid substitution. This was associated with loss of heterozygosity of the other allele. mutations EP300, PRO2221GLN number 2 clinvarAccessions RCV000007284;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 dbSnps rs137853039 text In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; {613684}), {25:Roelfsema et al. (2005)} found a de novo 1942C-T transition in exon 10 of the EP300 gene, resulting in an arg648-to-ter (R648X) mutation. mutations EP300, ARG648TER number 3 clinvarAccessions RCV000007285;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a patient with Rubinstein-Taybi syndrome-2 (RSTS2; {613684}), {25:Roelfsema et al. (2005)} found a de novo 8-bp deletion that removed nucleotides 2877-2884 from exon 15 of the EP300 gene. The 8-bp deletion resulted in a frameshift beginning at codon 959 and ending with a premature stop at codon 966. mutations EP300, 8-BP DEL, NT2877 number 4 clinvarAccessions RCV000007286;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a patient with Rubinstein-Taybi syndrome-2 ({613684}), {25:Roelfsema et al. (2005)} found a deletion of the first exon of the EP300 gene. It was considered probable that this deletion would lead to no expression from the affected allele. mutations EP300, EX1DEL number 5 clinvarAccessions RCV000007287;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a patient with Rubinstein-Taybi syndrome-2 ({613684}), {37:Zimmermann et al. (2007)} identified a 1-bp deletion (7100delC) in exon 31 of the EP300 gene, The patient had a 'mild' form of the disorder with higher intelligence than other reported patients (IQ estimated at 75) and mild facial dysmorphism. The mutation is located close to the 3-prime end of the protein, was predicted to be a mild truncation, and does not alter the HAT domain. mutations EP300, 1-BP DEL, 7100C number 6 clinvarAccessions RCV000007288;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a 7-year-old boy with global developmental delay, slightly broad halluces but normal thumbs, and facial dysmorphism reminiscent of Rubinstein-Taybi syndrome-2 ({613684}), especially while smiling, {9:Foley et al. (2009)} identified heterozygosity for a de novo deletion of exon 4 of the EP300 gene; RNA sequencing revealed that exon 2 was spliced to exon 9, indicating deletion of exons 3 through 8. Neither parent carried the deletion. mutations EP300, EX3-8DEL number 7 clinvarAccessions RCV000007289;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a 3-year-old boy with RSTS2 ({613684}), {5:Bartsch et al. (2010)} identified an apparently de novo heterozygous 1-bp deletion (638delG) in exon 2 of the EP300 gene, predicted to result in a frameshift and premature termination. The child had severe microcephaly, retrognathia, broad thumbs and great toes, and delayed psychomotor development with marked speech delay. He also had posterior helical pits but normal palpebral fissures, nose, and mouth. mutations EP300, 1-BP DEL, 638G number 8 clinvarAccessions RCV000023210;;1 status live name RUBINSTEIN-TAYBI SYNDROME 2 text In a 5-year-old Caucasian boy with a phenotype overlapping Cornelia de Lange syndrome ({122470}), {34:Woods et al. (2014)} made the molecular diagnosis of RSTS2 ({613684}) postmortem. Whole-exome sequencing identified a heterozygous c.104_107del mutation in exon 2 of the EP300 gene, resulting in a frameshift (Ser35fs). The mutation, which was confirmed by Sanger sequencing, was not found in either parent. mutations EP300, 4-BP DEL, NT104 number 9 clinvarAccessions RCV000125469;;1 prefix * titles alternativeTitles p300 preferredTitle E1A-BINDING PROTEIN, 300-KD; EP300 textSectionList textSection textSectionTitle Description textSectionContent The EP300 gene encodes p300, a histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation ({10:Gayther et al., 2000}). textSectionName description textSectionTitle Cloning textSectionContent The growth-controlling functions of the adenovirus E1A oncoprotein depend on its ability to interact with a set of cellular proteins. Among these are the retinoblastoma protein, p107, p130, and p300. {7:Eckner et al. (1994)} isolated a cDNA encoding full-length human p300. p300 contains 3 cysteine- and histidine-rich regions of which the most carboxy-terminal region interacts specifically with E1A. In its center, p300 contains a bromodomain, a hallmark of certain transcriptional coactivators. p300 and CREB-binding protein (CREBBP, or CBP; {600140}) are highly related in primary structure ({3:Arany et al., 1994}). Several protein motifs such as a bromodomain, a KIX domain, and 3 regions rich in cys/his residues are well conserved between these 2 proteins. textSectionName cloning textSectionTitle Biochemical Features textSectionContent {18:Lin et al. (2001)} identified a compactly folded 46-residue domain in CBP and p300, the IRF3-binding domain (IBID), and determined its structure by nuclear magnetic resonance spectroscopy. IBID has a helical framework containing an apparently flexible polyglutamine loop that participates in ligand binding. Spectroscopic data indicated that induced folding accompanies association of IBID with its partners, which exhibit no evident sequence similarities. IBID is an important contributor to signal integration by CBP and p300. Crystal Structure {20:Liu et al. (2008)} described a high resolution x-ray crystal structure of a semisynthetic heterodimeric p300 HAT domain in complex with a bisubstrate inhibitor, Lys-CoA. This structure showed that p300/CBP is a distant cousin of other structurally characterized HATs, but revealed several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, {20:Liu et al. (2008)} proposed that p300/CBP uses an unusual hit-and-run (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations could also be readily accounted for by the p300 HAT structure. textSectionName biochemicalFeatures textSectionTitle Gene Function textSectionContent {7:Eckner et al. (1994)} examined the ability of p300 to overcome the repressive effect of E1A on the SV40 enhancer. They showed that p300 molecules lacking an intact E1A-binding site can bypass E1A repression and restore to a significant extent the activity of the SV40 enhancer, even in the presence of high levels of E1A protein. These results imply that p300 may function as a transcriptional adaptor protein for certain complex transcriptional regulatory elements. {33:Weaver et al. (1998)} identified EP300/CREBBP and IRF3 ({603734}) as components of DRAF1 (double-stranded RNA-activated factor-1), a positive regulator of interferon-stimulated gene transcription that functions as a direct response to viral infection. The cytokines LIF ({159540}) and BMP2 ({112261}) signal through different receptors and transcription factors, namely STATs and SMADs, respectively. {23:Nakashima et al. (1999)} found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 interacted physically with STAT3 ({102582}) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 ({601595}) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors. {13:Hasan et al. (2001)} demonstrated that p300 may have a role in DNA repair synthesis through its interaction with proliferating cell nuclear antigen (PCNA; {176740}). {13:Hasan et al. (2001)} demonstrated that in vitro and in vivo p300 forms a complex with PCNA that does not depend on the S phase of the cell cycle. A large fraction of both p300 and PCNA colocalized to speckled structures in the nucleus. Furthermore, the endogenous p300-PCNA complex stimulates DNA synthesis in vitro. Chromatin immunoprecipitation experiments indicated that p300 is associated with freshly synthesized DNA after ultraviolet irradiation. {13:Hasan et al. (2001)} suggested the p300 may participate in chromatin remodeling at DNA lesion sites to facilitate PCNA function in DNA repair synthesis. {14:Hasan et al. (2001)} found that p300 formed a complex with flap endonuclease-1 (FEN1; {600393}) and acetylated FEN1 in vitro. Furthermore, FEN1 acetylation was observed in vivo and was enhanced upon ultraviolet treatment of human cells. Acetylation of the FEN1 C terminus by p300 significantly reduced DNA binding and nuclease activity of FEN1. PCNA was able to stimulate both acetylated and unacetylated FEN1 activity to the same extent. These results identified acetylation as a novel regulatory modification of FEN1 and suggested that p300 is not only a component of the chromatin remodeling machinery but might also play a critical role in regulating DNA metabolic events. TDG ({601423}) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. {27:Tini et al. (2002)} reported that TDG associates with transcriptional coactivators CBP ({600140}) and p300 and that the resulting complexes are competent for both the excision step of repair and histone acetylation. TDG stimulated CBP transcriptional activity in transfected cells and reciprocally served as a substrate for CBP/p300 acetylation. This acetylation triggered release of CBP from DNA ternary complexes and also regulated recruitment of repair endonuclease APE ({107748}). These observations revealed a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability. {8:Etchegaray et al. (2003)} demonstrated that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone (see {602810}) acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1 ({602260}), Per2 ({603426}), and Cry1 ({601933}) genes exhibited circadian rhythms in H3 acetylation and RNA polymerase II (see {180660}) binding that were synchronous with the corresponding steady-state mRNA rhythms. The histone acetyltransferase p300 precipitated with Clock ({601851}) in vivo in a time-dependent manner. Moreover, the Cry proteins inhibited a p300-induced increase in Clock/Bmal1 ({602550})-mediated transcription. {8:Etchegaray et al. (2003)} concluded that the delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, was due to the coordinated activities of Rev-Erb-alpha ({602408}) and Clock/Bmal1, and defined a novel mechanism for circadian phase control. Rapid turnover of the tumor suppressor protein p53 ({191170}) requires the MDM2 ({164785}) ubiquitin ligase, and both interact with p300-CBP transcriptional coactivators. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. {11:Grossman et al. (2003)} observed that purified p300 exhibited intrinsic ubiquitin ligase activity but was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, {11:Grossman et al. (2003)} concluded that generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300. {28:Tsuda et al. (2003)} found that SOX9 ({608160}) used CBP and p300 as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 ({120140}) promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes. Using systems reconstituted with recombinant chromatin templates and coactivators, {1:An et al. (2004)} demonstrated the involvement of PRMT1 ({602950}) and CARM1 ({603934}) in p53 function; both independent and ordered cooperative functions of p300, PRMT1, and CARM1; and mechanisms involving direct interactions with p53 and obligatory modifications of corresponding histone substrates. Chromatin immunoprecipitation analyses confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on a p53-responsive gene, GADD45 ({126335}), following ectopic p53 expression and/or ultraviolet irradiation. {29:Turnell et al. (2005)} showed that 2 anaphase-promoting complex/cyclosome (APC/C) components, APC5 ({606948}) and APC7 ({606949}), interact directly with the coactivators CBP and p300 through protein-protein interaction domains that are evolutionarily conserved in adenovirus E1A. This interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. {29:Turnell et al. (2005)} also showed that APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner, indicating that these components of the APC/C may be targeted during cellular transformation. Furthermore, {29:Turnell et al. (2005)} established that CBP is required for APC/C function; specifically, gene ablation of CBP by RNA-mediated interference markedly reduces the E3 ubiquitin ligase activity of the APC/C and the progression of cells through mitosis. Taken together, {29:Turnell et al. (2005)} concluded that their results define discrete roles for the APC/C-CBP/p300 complexes in growth regulation. In vivo transcription by RNA polymerase II takes place in the context of chromatin. {12:Guermah et al. (2006)} found that a purified, reconstituted RNA polymerase II system that sufficed for activator-dependent transcription on DNA templates was incapable of transcribing chromatin templates, even in the presence of factors that effected transcription in less-purified assay systems. Using a complementation and HeLa cell nuclear extract fractionation scheme, {12:Guermah et al. (2006)} identified and purified an activity, designated CTEA (chromatin transcription-enabling activity), that allowed for transcription through chromatin templates in a manner that was both activator and p300/acetyl-CoA dependent. CTEA acted primarily at the elongation step and enabled RNA polymerase II machinery to transcribe efficiently through several contiguously positioned nucleosomes. {12:Guermah et al. (2006)} identified the major functional component of CTEA as transcription elongation factor SII (TCEA1; {601425}). SII was essential for productive transcription elongation, and its function at this step was dependent on p300-dependent acetylation. These synergistic transcriptional elongation activities were potentiated by HMGB2 ({163906}). {21:Liu et al. (2008)} demonstrated that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin-1 (SIRT1; {604479}), maintains energy balance in mice through the sequential induction of CRTC2 ({608972}) and FOXO1 ({136533}). After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which {21:Liu et al. (2008)} showed is also activated by dephosphorylation at serine-89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at lysine-628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1; {608067}). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the SIRT1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator Ppar-gamma coactivator 1-alpha (PGC1-alpha; {604517}) by SIRT1 activators, {21:Liu et al. (2008)} concluded that their results illustrate how the exchange of 2 gluconeogenic regulators during fasting maintains energy balance. {31:Visel et al. (2009)} presented the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and mapped several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain, and limb tissue. They tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. {31:Visel et al. (2009)} concluded that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggested that such datasets will be useful in the study of the role of tissue-specific enhancers in human biology and disease on a genomewide scale. {6:Das et al. (2009)} demonstrated that the histone acetyltransferase CBP ({600140}) in flies, and CBP and p300 in humans, acetylate histone H3 (see {601128}) on lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 and SIRT2 ({604480}) deacetylate H3K56 acetylation. The histone chaperones ASF1A ({609189}) in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF1 (see {601245}) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. {6:Das et al. (2009)} showed that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumors. {6:Das et al. (2009)} concluded that their identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation, and cancer. {30:Vilhais-Neto et al. (2010)} found that RERE ({605226}) forms a complex with NR2F2 ({107773}), p300, and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the RARB ({180220}) promoter. Furthermore, the knockdown of NR2F2 and/or RERE decreases retinoic acid signaling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The symmetrical expression of NR2F2 in the presomitic mesoderm overlaps with the symmetry of the retinoic acid signaling response, supporting its implication in the control of somitic symmetry. {30:Vilhais-Neto et al. (2010)} suggested that misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis. {35:Xu et al. (2011)} isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices, and found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300, recruited via bone morphogenetic protein (BMP; see {600799}) signaling, and the histone methyltransferase Ezh2 ({601573}) have modulatory roles in the fate choice. {35:Xu et al. (2011)} concluded that their studies revealed a functional 'prepattern' of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction. {32:Wang et al. (2011)} found that AML1-ETO (see {151385}), a fusion protein generated by the t(8;21) translocation found in acute myelogenous leukemia, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34+ ({142230}) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. {32:Wang et al. (2011)} concluded that lysine acetyltransferases represent a potential therapeutic target in AML. To identify distant-acting enhancers active during craniofacial development, {4:Attanasio et al. (2013)} used chromatin immunoprecipitation on embryonic mouse face tissue followed by sequencing to identify noncoding genome regions bound by the enhancer-associated p300 protein. They identified more than 4,000 candidate enhancers, the majority of which were at least partially conserved between humans and mice. {4:Attanasio et al. (2013)} subsequently used LacZ reporter assays in transgenic mice and optical projection tomography to determine 3-dimensional expression patterns of a subset of these candidate enhancers. Further characterization of more than 200 candidate enhancer sequences in transgenic mice revealed a remarkable spatial complexity of in vivo expression patterns. Candidate enhancers were identified within the gene desert associated with cleft palate and facial morphology on chromosome 8q24, and at the ABCA4 ({601691}) locus. Targeted deletions of 3 craniofacial enhancers near genes with roles in craniofacial development (Snai2, {602150}; Msx1, {142983}; and Isl1, {600366}) resulted in changes of expression of those genes as well as quantitatively subtle yet definable alterations of craniofacial shape. textSectionName geneFunction textSectionTitle Mapping textSectionContent By fluorescence in situ hybridization, {7:Eckner et al. (1994)} mapped the p300 gene, symbolized EP300, to chromosome 22q13. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Role in Cancer A role for EP300 in cancer had been implied by the fact that it is targeted by viral oncoproteins ({2:Arany et al., 1995}), it is fused to MLL ({159555}) in leukemia ({15:Ida et al., 1997}), and 2 missense sequence alterations in EP300 were identified in epithelial malignancies ({22:Muraoka et al., 1996}). {10:Gayther et al. (2000)} described somatic EP300 mutations (see, e.g., {602700.0001}; {602700.0002}) that predicted a truncated protein in 6 (3%) of 193 epithelial cancers analyzed. Of these 6 mutations, 2 were in primary tumors (a colorectal cancer and a breast cancer) and 4 were in cancer cell lines (colorectal, breast, and pancreatic). In addition, they identified a somatic in-frame insertion in a primary breast cancer and missense alterations in a primary colorectal cancer and 2 cell lines (breast and pancreatic). Inactivation of the second allele was demonstrated in 5 of the 6 cases with truncating mutations and in 2 other cases. The data showed that EP300 is mutated in epithelial cancers and provided the first evidence that it behaves as a classic tumor suppressor gene. {24:Pasqualucci et al. (2011)} reported that the 2 most common types of B cell non-Hodgkin lymphoma ({605027}), follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. {24:Pasqualucci et al. (2011)} demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein ({109565}) and activation of the p53 tumor suppressor ({191170}). {17:Le Gallo et al. (2012)} used whole-exome sequencing to comprehensively search for somatic mutations in 13 primary serous endometrial tumors (see {608089}), and subsequently resequenced 18 genes that were mutated in more than 1 tumor and/or were components of an enriched functional grouping from 40 additional serous tumors. {17:Le Gallo et al. (2012)} identified a high frequency of somatic mutation (8%) in the EP300 gene. Rubinstein-Taybi Syndrome 2 In 3 unrelated patients with Rubinstein-Taybi syndrome-2 (RSTS2; {613684}), {25:Roelfsema et al. (2005)} identified 3 different heterozygous mutations in the EP300 gene ({602700.0003}-{602700.0005}). CREBBP and EP300 function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways. Inactivation of CREBBP also results in Rubinstein-Taybi syndrome-1 (RSTS1; {180849}), indicating that a certain level of the protein is essential for normal development. There is a direct link between loss of acetyltransferase activity and RSTS, which indicates the disorder is caused by aberrant chromatin regulation. {25:Roelfsema et al. (2005)} stated that these were the first mutations identified in EP300 underlying a congenital disorder. In 1 (2.6%) of 38 patients with RSTS who did not have mutations in the CREBBP gene, {37:Zimmermann et al. (2007)} identified a mutation in the EP300 gene ({602700.0006}) predicted to result in mild protein truncation. The patient had a very mild form of the disorder. {37:Zimmermann et al. (2007)} concluded that mutations in the EP300 gene play only a minor role in the etiology of RSTS. In a 7-year-old boy with suspected Rubinstein-Taybi syndrome in whom sequencing and MLPA analysis of the CREBBP gene was normal, {9:Foley et al. (2009)} identified a deletion involving exons 3 to 8 in the EP300 gene ({602700.0007}). textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent The transcriptional coactivator and integrator p300 and its closely related family member CREBBP mediate multiple signal-dependent transcriptional events. {36:Yao et al. (1998)} generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development. Cells derived from p300-deficient embryos displayed specific transcriptional defects and proliferated poorly. p300 heterozygotes also manifested considerable embryonic lethality. Moreover, double heterozygosity for p300 and CREBBP was invariably associated with embryonic death. Thus, mouse development is exquisitely sensitive to the overall gene dosage of p300 and CREBBP. These results provide evidence that a coactivator endowed with histone acetyltransferase activity is essential for mammalian cell proliferation and development. {16:Kasper et al. (2002)} demonstrated that the protein-binding KIX domains of CBP ({600140}) and p300 have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb ({189990}) and Creb ({123810}), multilineage defects occur in hematopoiesis, including anemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis, and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-MYB and mutations in the KIX domain of p300, which suggests that the binding of c-MYB to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, {16:Kasper et al. (2002)} concluded that conserved domains in 2 highly related coactivators have contrasting roles in hematopoiesis. {26:Sandberg et al. (2005)} created mice with a homozygous met303-to-val (M303V) mutation in the Myb gene, which disrupted the interaction between Myb and p300. The biologic consequences of the mutation included thrombocytosis, megakaryocytosis, anemia, lymphopenia, and absence of eosinophils. Detailed analysis of hematopoiesis in mutant mice revealed distinct blocks in T-cell, B-cell, and red blood cell development, as well as a 10-fold increase in the number of hematopoietic stem cells. Cell cycle analysis showed that twice as many mutant hematopoietic stem cells were actively cycling in mutant mice compared with wildtype mice. {26:Sandberg et al. (2005)} concluded that MYB, through its interaction with p300, controls the proliferation and differentiation of hematopoietic stem and progenitor cells. textSectionName animalModel textSectionTitle History textSectionContent {19:Lin et al. (2012)} reported that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), PRKAA1 ({602739}), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 ({601241}) and p300. Deacetylation of AMPK enhanced physical interaction with the upstream kinase LKB1 ({602216}), leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. The authors later found that the Methods section of their article was inaccurate. Because they could not reproduce all of their results, they retracted the article. textSectionName history geneMapExists true editHistory carol : 06/16/2014 alopez : 2/3/2014 alopez : 2/3/2014 carol : 11/7/2013 carol : 9/16/2013 mgross : 2/7/2013 alopez : 2/7/2013 alopez : 2/7/2013 mgross : 2/5/2013 alopez : 3/12/2012 terry : 3/7/2012 alopez : 9/2/2011 terry : 8/30/2011 alopez : 6/16/2011 terry : 6/14/2011 alopez : 6/13/2011 terry : 6/6/2011 wwang : 1/25/2011 ckniffin : 1/6/2011 alopez : 4/23/2010 terry : 4/22/2010 wwang : 3/10/2010 mgross : 3/8/2010 mgross : 1/4/2010 terry : 12/8/2009 carol : 11/5/2009 terry : 10/30/2009 terry : 9/9/2009 alopez : 6/4/2009 terry : 5/19/2009 alopez : 3/10/2009 terry : 3/9/2009 alopez : 12/10/2008 terry : 11/26/2008 alopez : 3/20/2008 wwang : 8/23/2007 ckniffin : 8/13/2007 ckniffin : 8/13/2007 ckniffin : 8/13/2007 alopez : 2/1/2006 terry : 1/30/2006 wwang : 3/18/2005 wwang : 3/14/2005 terry : 3/11/2005 mgross : 2/23/2005 mgross : 8/5/2004 alopez : 4/22/2003 terry : 4/22/2003 alopez : 2/24/2003 alopez : 2/24/2003 terry : 2/21/2003 alopez : 11/13/2002 terry : 11/12/2002 mgross : 9/23/2002 mgross : 11/5/2001 mgross : 7/3/2001 alopez : 3/14/2001 terry : 3/12/2001 mcapotos : 8/1/2000 alopez : 3/1/2000 terry : 3/1/2000 psherman : 4/16/1999 alopez : 4/15/1999 carol : 8/27/1998 carol : 6/11/1998 dateCreated Tue, 09 Jun 1998 03:00:00 EDT creationDate Stylianos E. Antonarakis : 6/9/1998 epochUpdated 1402902000 dateUpdated Mon, 16 Jun 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092867404004891 publisherName Elsevier Science title Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. mimNumber 602700 referenceNumber 1 publisherAbbreviation ES pubmedID 15186775 source Cell 117: 735-748, 2004. authors An, W., Kim, J., Roeder, R. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/374081a0 publisherName Nature Publishing Group title A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. mimNumber 602700 referenceNumber 2 publisherAbbreviation NPG pubmedID 7870178 source Nature 374: 81-84, 1995. authors Arany, Z., Newsome, D., Oldread, E., Livingston, D. M., Eckner, R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(94)90127-9 publisherName Elsevier Science title E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators. (Letter) mimNumber 602700 referenceNumber 3 publisherAbbreviation ES pubmedID 8004670 source Cell 77: 799-800, 1994. authors Arany, Z., Sellers, W. R., Livingston, D. M., Eckner, R. pubmedImages false publisherUrl http://www.elsevier.com/ source Science 342: :440 only, 2013. Note: Full article online. mimNumber 602700 authors Attanasio, C., Nord, A. S., Zhu, Y., Blow, M. J., Li, Z., Liberton, D. K., Morrison, H., Plajzer-Frick, I., Holt, A., Hosseini, R., Phouanenavong, S., Akiyama, J. A., Shoukry, M., Afzal, V., Rubin, E. M., FitzPatrick, D. R., Ren, B., Hallgrimsson, B., Pennacchio, L. A., Visel, A. title Fine tuning of craniofacial morphology by distant-acting enhancers. referenceNumber 4 articleUrl http://dx.doi.org/10.1002/ajmg.a.33153 publisherName John Wiley & Sons, Inc. title Two patients with EP300 mutations and facial dysmorphism different from the classic Rubinstein-Taybi syndrome. mimNumber 602700 referenceNumber 5 publisherAbbreviation Wiley pubmedID 20014264 source Am. J. Med. Genet. 152A: 181-184, 2010. authors Bartsch, O., Labonte, J., Albrecht, B., Wieczorek, D., Lechno, S., Zechner, U., Haaf, T. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/nature07861 publisherName Nature Publishing Group title CBP/p300-mediated acetylation of histone H3 on lysine56. mimNumber 602700 referenceNumber 6 publisherAbbreviation NPG pubmedID 19270680 source Nature 459: 113-117, 2009. Note: Erratum: Nature 460: 1164 only, 2009. authors Das, C., Lucia, M. S., Hansen, K. C., Tyler, J. K. pubmedImages false publisherUrl http://www.nature.com source Genes Dev. 15: 869-884, 1994. mimNumber 602700 authors Eckner, R., Ewen, M. E., Newsome, D., Gerdes, M., DeCaprio, J. A., Lawrence, J. B., Livingston, D. M. title Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. referenceNumber 7 articleUrl http://dx.doi.org/10.1038/nature01314 publisherName Nature Publishing Group title Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. mimNumber 602700 referenceNumber 8 publisherAbbreviation NPG pubmedID 12483227 source Nature 421: 177-182, 2003. authors Etchegaray, J.-P., Lee, C., Wade, P. A., Reppert, S. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.32771 publisherName John Wiley & Sons, Inc. title Further case of Rubinstein-Taybi syndrome due to a deletion in EP300. mimNumber 602700 referenceNumber 9 publisherAbbreviation Wiley pubmedID 19353645 source Am. J. Med. Genet. 149A: 997-1000, 2009. authors Foley, P., Bunyan, D., Stratton, J., Dillon, M., Lynch, S. A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/73536 publisherName Nature Publishing Group title Mutations truncating the EP300 acetylase in human cancers. mimNumber 602700 referenceNumber 10 publisherAbbreviation NPG pubmedID 10700188 source Nature Genet. 24: 300-303, 2000. authors Gayther, S. A., Batley, S. J., Linger, L., Bannister, A., Thorpe, K., Chin, S.-F., Daigo, Y., Russell, P., Wilson, A., Sowter, H. M., Delhanty, J. D. A., Ponder, B. A. J., Kouzarides, T., Caldas, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=12690203 publisherName HighWire Press title Polyubiquitination of p53 by a ubiquitin ligase activity of p300. mimNumber 602700 referenceNumber 11 publisherAbbreviation HighWire pubmedID 12690203 source Science 300: 342-344, 2003. authors Grossman, S. R., Deato, M. E., Brignone, C., Chan, H. M., Kung, A. L., Tagami, H., Nakatani, Y., Livingston, D. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(06)00377-1 publisherName Elsevier Science title Synergistic functions of SII and p300 in productive activator-dependent transcription of chromatin templates. mimNumber 602700 referenceNumber 12 publisherAbbreviation ES pubmedID 16630816 source Cell 125: 275-286, 2006. authors Guermah, M., Palhan, V. B., Tackett, A. J., Chait, B. T., Roeder, R. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/35066610 publisherName Nature Publishing Group title Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis. mimNumber 602700 referenceNumber 13 publisherAbbreviation NPG pubmedID 11268218 source Nature 410: 387-391, 2001. authors Hasan, S., Hassa, P. O., Imhof, R., Hottiger, M. O. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(01)00272-6 publisherName Elsevier Science title Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. mimNumber 602700 referenceNumber 14 publisherAbbreviation ES pubmedID 11430825 source Molec. Cell 7: 1221-1231, 2001. authors Hasan, S., Stucki, M., Hassa, P. O., Imhof, R., Gehrig, P., Hunziker, P., Hubscher, U., Hottiger, M. O. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9389684 publisherName HighWire Press title Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). mimNumber 602700 referenceNumber 15 publisherAbbreviation HighWire pubmedID 9389684 source Blood 90: 4699-4704, 1997. authors Ida, K., Kitabayashi, I., Taki, T., Taniwaki, M., Noro, K., Yamamoto, M., Ohki, M., Hayashi, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature01062 publisherName Nature Publishing Group title A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. mimNumber 602700 referenceNumber 16 publisherAbbreviation NPG pubmedID 12384703 source Nature 419: 738-743, 2002. authors Kasper, L. H., Boussouar, F., Ney, P. A., Jackson, C. W., Rehg, J., van Deursen, J. M., Brindle, P. K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng.2455 publisherName Nature Publishing Group title Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. mimNumber 602700 referenceNumber 17 publisherAbbreviation NPG pubmedID 23104009 source Nature Genet. 44: 1310-1315, 2012. authors Le Gallo, M., O'Hara, A. J., Rudd, M. L., Urick, M. E., Hansen, N. F., O'Neil, N. J., Price, J. C., Zhang, S., England, B. M., Godwin, A. K., Sgroi, D. C., {NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program}, Hieter, P., Mullikan, J. C., Merino, M. J., Bell, D. W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(01)00333-1 publisherName Elsevier Science title A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies. mimNumber 602700 referenceNumber 18 publisherAbbreviation ES pubmedID 11583620 source Molec. Cell 8: 581-590, 2001. authors Lin, C. H., Hare, B. J., Wagner, G., Harrison, S. C., Maniatis, T., Fraenkel, E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nature10804 publisherName Nature Publishing Group title Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. mimNumber 602700 referenceNumber 19 publisherAbbreviation NPG pubmedID 22318606 source Nature 482: 251-255, 2012. Note: Retraction: Nature 503: 146 only, 2013. authors Lin, Y., Kiihl, S., Suhail, Y., Liu, S.-Y., Chou, Y., Kuang, Z., Lu, J., Khor, C. N., Lin, C.-L., Bader, J. S., Irizarry, R., Boeke, J. D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature06546 publisherName Nature Publishing Group title The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. mimNumber 602700 referenceNumber 20 publisherAbbreviation NPG pubmedID 18273021 source Nature 451: 846-850, 2008. authors Liu, X., Wang, L., Zhao, K., Thompson, P. R., Hwang, Y., Marmorstein, R., Cole, P. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature07349 publisherName Nature Publishing Group title A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. mimNumber 602700 referenceNumber 21 publisherAbbreviation NPG pubmedID 18849969 source Nature 456: 269-273, 2008. authors Liu, Y., Dentin, R., Chen, D., Hedrick, S., Ravnskjaer, K., Schenk, S., Milne, J., Meyers, D. J., Cole, P., Yates, J., III, Olefsky, J., Guarente, L., Montminy, M. pubmedImages false publisherUrl http://www.nature.com title p300 gene alterations in colorectal and gastric carcinomas. mimNumber 602700 referenceNumber 22 pubmedID 8622873 source Oncogene 12: 1565-1569, 1996. authors Muraoka, M., Konishi, M., Kikuchi-Yanoshita, R., Tanaka, K., Shitara, N., Chong, J.-M., Iwama, T., Miyaki, M. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=10205054 publisherName HighWire Press title Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. mimNumber 602700 referenceNumber 23 publisherAbbreviation HighWire pubmedID 10205054 source Science 284: 479-482, 1999. authors Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., Taga, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature09730 publisherName Nature Publishing Group title Inactivating mutations of acetyltransferase genes in B-cell lymphoma. mimNumber 602700 referenceNumber 24 publisherAbbreviation NPG pubmedID 21390126 source Nature 471: 189-195, 2011. authors Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62869-9 publisherName Elsevier Science title Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. mimNumber 602700 referenceNumber 25 publisherAbbreviation ES pubmedID 15706485 source Am. J. Hum. Genet. 76: 572-580, 2005. authors Roelfsema, J. H., White, S. J., Ariyurek, Y., Bartholdi, D., Niedrist, D., Papadia, F., Bacino, C. A., den Dunnen, J. T., van Ommen, G.-J. B., Breuning, M. H., Hennekam, R. C., Peters, D. J. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1534-5807(04)00467-8 publisherName Elsevier Science title c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. mimNumber 602700 referenceNumber 26 publisherAbbreviation ES pubmedID 15691758 source Dev. Cell 8: 153-166, 2005. authors Sandberg, M. L., Sutton, S. E., Pletcher, M. T., Wiltshire, T., Tarantino, L. M., Hogenesch, J. B., Cooke, M. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097276502004537 publisherName Elsevier Science title Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. mimNumber 602700 referenceNumber 27 publisherAbbreviation ES pubmedID 11864601 source Molec. Cell 9: 265-277, 2002. authors Tini, M., Benecke, A., Um, S.-J., Torchia, J., Evans, R. M., Chambon, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12732631 publisherName HighWire Press title Transcriptional co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9. mimNumber 602700 referenceNumber 28 publisherAbbreviation HighWire pubmedID 12732631 source J. Biol. Chem. 278: 27224-27229, 2003. authors Tsuda, M., Takahashi, S., Takahashi, Y., Asahara, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature04151 publisherName Nature Publishing Group title The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression. mimNumber 602700 referenceNumber 29 publisherAbbreviation NPG pubmedID 16319895 source Nature 438: 690-695, 2005. authors Turnell, A. S., Stewart, G. S., Grand, R. J. A., Rookes, S. M., Martin, A., Yamano, H., Elledge, S. J., Gallimore, P. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature08763 publisherName Nature Publishing Group title Rere controls retinoic acid signalling and somite bilateral symmetry. mimNumber 602700 referenceNumber 30 publisherAbbreviation NPG pubmedID 20164929 source Nature 463: 953-957, 2010. authors Vilhais-Neto, G. C., Maruhashi, M., Smith, K. T., Vasseur-Cognet, M., Peterson, A. S., Workman, J. L., Pourquie, O. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature07730 publisherName Nature Publishing Group title ChIP-seq accurately predicts tissue-specific activity of enhancers. mimNumber 602700 referenceNumber 31 publisherAbbreviation NPG pubmedID 19212405 source Nature 457: 854-858, 2009. authors Visel, A., Blow, M. J., Li, Z., Zhang, T., Akiyama, J. A., Holt, A., Plajzer-Frick, I., Shoukry, M., Wright, C., Chen, F., Afzal, V., Ren, B., Rubin, E. M., Pennacchio, L. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=21764752 publisherName HighWire Press title The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. mimNumber 602700 referenceNumber 32 publisherAbbreviation HighWire pubmedID 21764752 source Science 333: 765-769, 2011. authors Wang, L., Gural, A., Sun, X.-J., Zhao, X., Perna, F., Huang, G., Hatlen, M. A., Vu, L., Liu, F., Xu, H., Asai, T., Xu, H., {and 9 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=9488451 publisherName HighWire Press title Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1. mimNumber 602700 referenceNumber 33 publisherAbbreviation HighWire pubmedID 9488451 source Molec. Cell. Biol. 18: 1359-1368, 1998. authors Weaver, B. K., Kumar, K. P., Reich, N. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.36237 publisherName John Wiley & Sons, Inc. title Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome. mimNumber 602700 referenceNumber 34 publisherAbbreviation Wiley pubmedID 24352918 source Am. J. Med. Genet. 164A: 251-258, 2014. authors Woods, S. A., Robinson, H. B., Kohler, L. J., Agamanolis, D., Sterbenz, G., Khalifa, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=21596989 publisherName HighWire Press title Chromatin 'prepattern' and histone modifiers in a fate choice for liver and pancreas. mimNumber 602700 referenceNumber 35 publisherAbbreviation HighWire pubmedID 21596989 source Science 332: 963-966, 2011. authors Xu, C.-R., Cole, P. A., Meyers, D. J., Kormish, J., Dent, S., Zaret, K. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)81165-4 publisherName Elsevier Science title Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. mimNumber 602700 referenceNumber 36 publisherAbbreviation ES pubmedID 9590171 source Cell 93: 361-372, 1998. authors Yao, T. P., Oh, S. P., Fuchs, M., Zhou, N.-D., Ch'ng, L.-E., Newsome, D., Bronson, R. T., Li, E., Livingston, D. M., Eckner, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201791 publisherName Nature Publishing Group title Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome. mimNumber 602700 referenceNumber 37 publisherAbbreviation NPG pubmedID 17299436 source Europ. J. Hum. Genet. 15: 837-842, 2007. authors Zimmermann, N., Acosta, A. M. B. F., Kohlhase, J., Bartsch, O. pubmedImages false publisherUrl http://www.nature.com externalLinks cmgGene false mgiHumanDisease false hprdIDs 04078 nbkIDs NBK1526;;Rubinstein-Taybi Syndrome refSeqAccessionIDs NG_009817.1 uniGenes Hs.517517,Hs.655211 approvedGeneSymbols EP300 nextGxDx true locusSpecificDBs http://www.LOVD.nl/EP300;;EP300 - Rubinstein-Taybi Syndrome (RSTS) dermAtlas false umlsIDs C1333336 gtr true geneIDs 2033 swissProtIDs Q09472 zfinIDs ZDB-GENE-080403-16,ZDB-GENE-080403-15 ensemblIDs ENSG00000100393,ENST00000263253 geneTests true mgiIDs MGI:1276116 ncbiReferenceSequences 189011537 genbankNucleotideSequences 77998116,22345942,495300,168277763,24727743,5870622,71516043,148136542,148136543,22336090,3961964,28140729,21167253,4775634,225000053,82137158,31753088,954917,134274223,28098142,47294691,1859631,511786937,511786936,33210947,47294696,511786938,1201385,5834596 proteinSequences 134274224,495301,77998117,168277764,31753089,223590203,578837003,119580812,50345997,225000054 geneticsHomeReferenceIDs gene;;EP300;;EP300

entryList

entry status live allelicVariantExists true epochCreated 1113462000 geneMap geneSymbols MSH2, COCA1, FCC1, HNPCC1 sequenceID 1685 phenotypeMapList phenotypeMap phenotypeMimNumber 120435 mimNumber 609309 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 120435 phenotypeMappingKey 3 phenotype Colorectal cancer, hereditary nonpolyposis, type 1 phenotypeMappingKey 3 mimNumber 609309 phenotypeInheritance Autosomal recessive phenotype Mismatch repair cancer syndrome phenotypeMimNumber 276300 phenotypeMappingKey 3 mimNumber 609309 phenotypeInheritance Autosomal dominant phenotype Muir-Torre syndrome phenotypeMimNumber 158320 chromosomeLocationStart 47630205 chromosomeSort 187 chromosomeSymbol 2 mimNumber 609309 geneInheritance None confidence C mappingMethod Fd, REa, Ch geneName mutS, E. coli, homolog of, 2 mouseMgiID MGI:101816 mouseGeneSymbol Msh2 computedCytoLocation 2p21 cytoLocation 2p22-p21 transcript uc002rvy.2 chromosomeLocationEnd 47739715 chromosome 2 contributors Cassandra L. Kniffin - updated : 2/17/2014 Cassandra L. Kniffin - updated : 3/20/2013 Cassandra L. Kniffin - updated : 12/3/2010 Cassandra L. Kniffin - updated : 8/28/2009 Cassandra L. Kniffin - updated : 2/18/2009 Marla J. F. O'Neill - updated : 1/18/2008 George E. Tiller - updated : 11/8/2007 George E. Tiller - updated : 5/21/2007 Victor A. McKusick - updated : 11/1/2006 Victor A. McKusick - updated : 10/26/2006 Cassandra L. Kniffin - updated : 5/17/2006 Victor A. McKusick - updated : 3/7/2006 Cassandra L. Kniffin - updated : 2/8/2006 Marla J. F. O'Neill - updated : 11/28/2005 Patricia A. Hartz - updated : 11/9/2005 Victor A. McKusick - updated : 7/6/2005 clinicalSynopsisExists false mimNumber 609309 allelicVariantList allelicVariant status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs28929483 text In family J living in New Zealand and studied by {49:Peltomaki et al. (1993)} for demonstration of linkage of colorectal cancer (HNPCC1; {120435}) to chromosome 2, {32:Leach et al. (1993)} demonstrated a CCA-to-CTA transition in codon 622, resulting in substitution of leucine for proline. The mutation was present in 1 allele of individual J-42, who was afflicted with colon and endometrial cancer at ages 42 and 44, respectively. All 11 affected individuals in the family had the mutation, while all 10 unaffected members and 20 unrelated individuals had proline at codon 622. mutations MSH2, PRO622LEU number 1 clinvarAccessions RCV000001823;;1;;;RCV000076307;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 text In studies of DNA from family C, a North American family with HNPCC1 ({120435}) studied by {49:Peltomaki et al. (1993)}, {32:Leach et al. (1993)} found no mutations of the conserved region of MSH2. A presumptive splicing defect was found that removed codons 265 to 314 from the MSH2 transcript. mutations MSH2, DEL 50 CODONS number 2 clinvarAccessions RCV000001824;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs63751108 text In a kindred with hereditary nonpolyposis colorectal cancer and linkage to 2p (HNPCC1; {120435}), {32:Leach et al. (1993)} demonstrated a CGA-to-TGA transition in codon 406, resulting in change of arginine to a stop. mutations MSH2, ARG406TER number 3 clinvarAccessions RCV000030238;;3;;;RCV000001825;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs121434320,rs28929484 text In a family with hereditary nonpolyposis colorectal cancer linked to 2p (HNPCC1; {120435}), {32:Leach et al. (1993)} demonstrated a CAT-to-TAT transition in codon 639, resulting in substitution of tyrosine for histidine. Of interest was the finding that, in addition to the germline mutation, an RER(+) tumor had a somatic mutation: substitution of TG for A in codon 663 (ATG), resulting in a frameshift. mutations MSH2, HIS639TYR number 4 clinvarAccessions RCV000030246;;3;;;RCV000001826;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs63749831 text In a family in which 3 first-degree relatives developed colon cancer (HNPCC1; {120435}) under the age of 45 years, with all neoplasms being mucinous adenocarcinomas, {41:Mary et al. (1994)} found deletion of codon 596 (AAT) resulting in the deletion of an asparagine residue from the protein. mutations MSH2, 3-BP DEL, ASN596DEL number 5 clinvarAccessions RCV000001827;;1;;;RCV000076285;;3;;;RCV000128908;;1 status live name MUIR-TORRE SYNDROME dbSnps rs63750047 text In a kindred with characteristics of the Muir-Torre syndrome ({158320}), {28:Kolodner et al. (1994)} found a C-to-T transition at nucleotide 1801 converting codon 601 from gln to stop. Thus, a truncated MSH2 protein was predicted. The affected members were heterozygous. This was 1 of 2 families in which all individuals in whom colorectal or endometrial cancers occurred were found to carry the mutant allele. Many of those carrying MSH2 mutations had tumors outside the colorectum, e.g., stomach cancer and small bowel cancer, and there were skin lesions characteristic of Muir-Torre syndrome. mutations MSH2, GLN601TER number 6 clinvarAccessions RCV000076290;;3;;;RCV000001828;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs63751207 text In a 38-year-old woman with serous cystadenocarcinoma of the ovary, {46:Orth et al. (1994)} found constitutional heterozygosity for an arg524-to-pro mutation of the MSH2 gene. Whereas normal tissue carried both mutant and wildtype alleles, the DNA isolated either from the patient's ovarian tumor or from the derived cell line carried only the mutant allele of the MSH2 gene. {46:Orth et al. (1994)} concluded that the woman probably had hereditary nonpolyposis colorectal cancer (HNPCC1; {120435}), of which ovarian cancer is an integral lesion. mutations MSH2, ARG524PRO number 7 clinvarAccessions RCV000076197;;3;;;RCV000001829;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs63749811 text In 2 apparently unrelated families with familial nonpolyposis colon cancer type 1 (HNPCC1; {120435}), {25:Jeon et al. (1996)} found the same mutation in exon 13 of the MSH2 gene: deletion of a single nucleotide from codon 705, changing TGT to TT. Exon 13 of the MSH2 gene was chosen for screening because it is in the middle of the most conserved region of the gene. The 2 families did not fulfill the strict Amsterdam criteria for HNPCC because each had an unaffected individual over the age of 50 with the mutation. mutations MSH2, 1-BP DEL number 8 clinvarAccessions RCV000030250;;3;;;RCV000001830;;1 status live name MUIR-TORRE SYNDROME dbSnps rs587776529 text {16:Esche et al. (1997)} described the case of a 62-year-old man with Muir-Torre syndrome ({158320}) who had rectal cancer, 2 keratoacanthomas, and multiple sebaceous adenomas, epitheliomas, and sebaceous hyperplasia. His brother and father died of colorectal cancer. A frameshift mutation leading to a truncated protein was demonstrated in the mismatch repair gene MSH2. One allele contained an insertion of 22 bp at codon 97 (after nucleotide 289) leading to a frameshift with a stop after 9 further codons. Presymptomatic molecular diagnosis could be offered to the children of the patient. mutations MSH2, 22-BP INS number 9 clinvarAccessions RCV000001831;;1;;;RCV000076538;;3 status live name MSH2 POLYMORPHISM dbSnps rs4987188 text {36:Liu et al. (1998)} concluded that gly322 to asp is a common polymorphism of the MSH2 gene and not a disease-causing mutation. They found this exon 6 mutation in 9 of 170 colorectal cancer (see {114500}) patients (5.3%) from high-risk families, and in 6 of those families this alteration was shown not to segregate with disease. They also found this alteration in 12 of 192 normal controls (6.3%) and in none of 104 sporadic colorectal cancer cases. mutations MSH2, GLY322ASP number 10 clinvarAccessions RCV000144615;;1;;;RCV000034561;;2;;;RCV000121567;;0;;;RCV000030257;;3;;;RCV000001832;;1 status live name COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 text {20:Froggatt et al. (1999)} reported an A-to-T transversion at nucleotide 943+3 of the MSH2 gene disrupting the 3-prime splice site of exon 5 and leading to deletion of this exon from the MSH2 mRNA. This mutation was originally identified in 3 of 29 North American HNPCC (HNPCC1; {120435}) families ({35:Liu et al., 1994}) and had also been found in 4 of 52 English families and in 10 of 20 families from Newfoundland. {20:Froggatt et al. (1999)} stated that this was the most common MSH2 mutation reported to that time. To investigate the origin of this mutation in these families, {20:Froggatt et al. (1999)} performed haplotype analysis using microsatellite markers linked to MSH2. A common haplotype was identified in 8 of the Newfoundland families, suggesting a founder effect. {20:Froggatt et al. (1999)} calculated age-related risks of all, colorectal, endometrial, and ovarian cancers in 76 carriers of the nucleotide 943+3 A-to-T MSH2 mutation for all patients and for men and women separately. For both sexes combined, the penetrance at age 60 years for all cancers and colorectal cancers was 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (P = less than 0.01) in males than in females. For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). In a note added in proof, {20:Froggatt et al. (1999)} reported that another 21 HNPCC families had been identified in Newfoundland, 1 of which carried the 943+3A-T mutation, raising the proportion of Newfoundland families with this mutation to 11 of 41 (27%). Three of these families were shown to have a common ancestor, and another common ancestor was found for an additional 2 families. {11:Desai et al. (2000)} studied 10 families from England, Italy, Hong Kong, and Japan with this mutation. Haplotype sharing was not apparent even within the European and the Asian kindreds. The authors concluded that the 943+3A-T mutation occurs de novo with relatively high frequency and hypothesized that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenine residues, of which the mutated A is the first. mutations MSH2, DEL EXON 5 number 11 clinvarAccessions RCV000001833;;1;;;RCV000030256;;3;;;RCV000078424;;1;;;RCV000001844;;1;;;RCV000115549;;2 status live name COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 dbSnps rs63750875 text In an Ashkenazi kindred with HNPCC ({120435}), {73:Yuan et al. (1999)} found a G-to-C transversion in the MSH2 gene, resulting in an ala636-to-pro (A636P) substitution segregating with the disease. In addition, they found a missense mutation in the APC gene (I1307K; {175100.0029}) in 2 unaffected members of the kindred. {73:Yuan et al. (1999)} concluded that clinical surveillance for CRC should not be discontinued in Ashkenazi families with HNPCC where an MSH2 mutation had been found until the APC gene had also been analyzed, and that the APC I1307K mutation should be sought in Ashkenazi families with multiple cases of CRC. {73:Yuan et al. (1999)} also recognized that the relationship between the presence of that mutation and CRC was not fully resolved. {19:Foulkes et al. (2002)} stated that the 1906G-C mutation had been found in 25 apparently unrelated Ashkenazi Jewish families. It was estimated to account for 2 to 3% of colorectal cancer in those whose age at diagnosis was less than 60 years. The mutation was highly penetrant and accounted for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfilled the Amsterdam criteria. Using an intraallelic coalescent model of multipoint linkage disequilibrium mapping, {56:Sun et al. (2005)} determined that the 1906G-C founder mutation probably originated between 1440 and 1715 in the Ashkenazi Jewish population, at a time when the Ashkenazim were living in eastern Europe in partially closed communities. mutations MSH2, ALA636PRO number 12 clinvarAccessions RCV000001834;;1;;;RCV000030245;;3;;;RCV000130428;;1 status live name COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 text In the historic family G with HNPCC ({120435}) of {68:Warthin (1913)}, {72:Yan et al. (2000)} identified a 24-bp insertion in the MSH2 gene by use of a method that converted cells from diploidy to haploidy. The insertion occurred between codons 215 and 216 of the cDNA resulting in a change in the splice acceptor of exon 4. mutations MSH2, 24-BP INS number 13 clinvarAccessions RCV000001835;;1 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs267607970 text {70:Whiteside et al. (2002)} reported a male infant who presented at 24 months of age with failure to thrive and a gastrointestinal infection that led to the diagnosis of T-cell acute lymphoblastic leukemia and IgA deficiency. He was also noted to have multiple cafe-au-lait spots, present from birth, of a size and number sufficient to satisfy one of the criteria for the diagnosis of NF1 ({162200}). However, he had no neurofibromas, axillary or inguinal freckling, Lisch nodules, optic glioma, sphenoid wing dysplasia, pseudarthrosis, or previous history of malignancy. His parents were nonconsanguineous but were from the same ethnic, religious, and geographic background. The phenotype was consistent with the mismatch repair cancer syndrome ({276300}), which has cafe-au-lait spots and hematologic malignancies as part of the spectrum. A homozygous G-to-A transition was found in the proband in the invariant G of the intron 10 acceptor site of the MSH2 gene. This mutation at position 1662-1 bp (relative to the ATG translational start site) was predicted to result in skipping of exon 11 to exon 12, with out-of-frame translation of the mutant mRNA resulting in a truncated, nonfunctional protein. The parents, who were both heterozygous for the mutation, did not have HNPCC, but the authors noted that their young age may explain the lack of observed cancer at that time. {2:Andrew (2002)} stated that the family reported by {70:Whiteside et al. (2002)} was of East Indian descent and lived in Alberta; the family had moved to Canada from Fiji. mutations MSH2, IVS10, G-A, -1 number 14 clinvarAccessions RCV000001836;;1;;;RCV000076224;;3 status live name MISMATCH REPAIR CANCER SYNDROME text {7:Bougeard et al. (2003)} described 2 sibs, a female who died of mediastinal T-cell lymphoma at the age of 15 months and her brother who died at age 4 years from a temporal glioblastoma. The phenotype was consistent with mismatch repair cancer syndrome ({276300}). The unaffected father was heterozygous for a genomic deletion removing exons 1-6 of the MSH2 gene; the unaffected mother was heterozygous for a 1-bp deletion at codon 153 within exon 3 of the MSH2 gene ({609309.0016}). Study of glioblastoma DNA from the boy indicated compound heterozygosity for the 2 parental mutations. In this family, endometrial carcinoma was the cause of death at age 43 years in an aunt of the mother and at age 59 years in the grandmother of the father. Furthermore, an uncle of the father had died of astrocytoma at age 27 years. In 2 sibs with adult-onset Lynch syndrome characterized by multiple colorectal cancers and adenomas, a small bowel carcinoma, and endometrial cancer ({120435}), {27:Kets et al. (2009)} found compound heterozygosity for 2 variants in the MSH2 gene: an exon 1-6 deletion and 1A-G transition in the initiation codon. The carcinomas showed microsatellite instability. {27:Kets et al. (2009)} noted that the phenotype in these sibs was not characteristic of the childhood cancer syndrome typically associated with biallelic MSH2 mutations, suggesting that the 1A-G transition retains residual protein activity, most likely through use of an alternative initiation codon 26 residues downstream. In addition, their healthy 80-year-old mother was heterozygous for the 1A-G transition. mutations MSH2, EX1-6 DEL number 15 alternativeNames COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1, INCLUDED clinvarAccessions RCV000001837;;1;;;RCV000023765;;1 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs63751449 text See {609309.0015} and {7:Bougeard et al. (2003)}. mutations MSH2, 1-BP DEL number 16 clinvarAccessions RCV000001839;;1;;;RCV000076602;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 text In affected members of 2 generations of an Ohio family with HNPCC ({120435}), {51:Pyatt et al. (2003)} identified a genomic deletion of approximately 11.4 kb encompassing the first 2 exons of the MSH2 gene. By Southern blot analysis, using a cDNA probe spanning the first 7 exons of MSH2, an alteration in each of 3 different enzyme digests was observed (including a unique 13-kb band on Hind III digests), which suggested the presence of a large alteration in the 5-prime region of the gene. The authors then generated mouse-human cell hybrids from a mutation carrier which contained a single copy each of human chromosome 2, upon which the MSH2 gene resides. Southern blots of DNA from the cell hybrids demonstrated the same unique 13-kb band from 1 MSH2 allele, as seen in the diploid DNA. DNA from this same monosomal cell hybrid failed to amplify in PCR using primers to exons 1 and 2, demonstrating the deletion of these sequences in 1 MSH2 allele, and the breakpoints involving Alu repeats were identified by PCR amplification and sequence analysis. mutations MSH2, 11.4-KB DEL number 17 clinvarAccessions RCV000001840;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 text In about 10% of North American families with HNPCC ({120435}), {63:Wagner et al. (2003)} found a 16-kb deletion encompassing exons 1-6 of the MSH2 gene. {38:Lynch et al. (2004)} noted that the breakpoints of the 16-kb deletion are 1 kb upstream of exon 1 and in intron 6. In most of the families the haplotype of the deleted allele was shared. By genealogic studies, a common ancestor could be traced for 5 of the 9 families found to have the MSH2 exon 1-6 founder deletion. The alleged ancestor was born around 1814 in Alabama and was presumably of German origin. He married and became a Mormon and had many children distributed over a rather wide geographic area. {38:Lynch et al. (2004)} reported that to date 61 of 566 family members of the 9 probands have been found to carry the 16-kb deletion. Three families have been genealogically shown to descend from a German immigrant family that settled in Pennsylvania in the early 1700s. Movements of branches of the extended family have been documented across the U.S. The 16-kb deletion was not found among 407 European and Australian families with HNPCC. mutations MSH2, 16-KB DEL, EX1-6 number 18 clinvarAccessions RCV000001841;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs587776530 text {9:Chan et al. (2004)} reported that in the southern Chinese population, a germline 4-bp deletion in the MSH2 gene, 1452delAATG, constitutes 21% of all germline mismatch repair gene mutations and 36% of all MSH2 germline mutations identified. In 10 families with HNPCC ({120435}) caused by the 4-bp deletion, haplotype analysis demonstrated the same disease haplotype, suggesting a founder effect. The 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of more than 93 million. {9:Chan et al. (2004)} estimated that the founder mutation occurred 22 to 103 generations ago. The mutation had not been identified in other ethnic groups. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide. mutations MSH2, 4-BP DEL, 1452AATG number 19 clinvarAccessions RCV000001842;;1;;;RCV000076166;;3 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs267607990 text In 2 brothers, born of consanguineous Pakistani parents, with early-onset HNPCC and cafe-au-lait spots, consistent with the mismatch repair cancer syndrome ({276300}), {43:Muller et al. (2006)} identified a homozygous T-to-A transversion in intron 12 of the MSH2 gene. The mutation is predicted to create an aberrant splice site, resulting in the skipping of exon 13 and creation of a premature stop codon at position 676, thus producing a truncated protein. Each unaffected parent was heterozygous for the mutation. Both boys were found to have numerous gastrointestinal polyps and carcinomas at age 11 and 12 years, respectively, as well as multiple cafe-au-lait spots. Neither had additional hematologic malignancies or brain tumors. mutations MSH2, IVS12AS, T-A, -5 number 20 clinvarAccessions RCV000001843;;1;;;RCV000076351;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs193922376 text {30:Kurzawski et al. (2006)} screened 226 patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC ({120435}) criteria for MSH2 and MLH1 ({120436}) germline mutations. They found 50 different pathogenic mutations, 25 in MSH2 and 25 in MLH1. The most frequent alteration was a change of A to T at the splice donor site of intron 5 of MSH2, found in 10 families. {57:Tang et al. (2009)} identified the A-to-T mutation in intron 5 of the MSH2 gene in a Taiwanese family with HNPCC, suggesting that it may be a mutation hotspot. mutations MSH2, IVS5DS, A-T, +3 number 21 clinvarAccessions RCV000115549;;2;;;RCV000030256;;3;;;RCV000078424;;1;;;RCV000001833;;1;;;RCV000001844;;1 status moved number 22 name MOVED TO {185535.0006} movedTo 185535.0006 status live name MUIR-TORRE SYNDROME text {4:Barana et al. (2004)} identified a 32-kb deletion involving exons 1-6 of the MSH2 gene in 3 affected members in 2 generations of an Italian family with Muir-Torre syndrome (MRTES; {158320}). The father had 2 metachronous colon cancers starting at age 53 years, a daughter had a colon and ovarian cancer starting at age 42 years, and a son had an adenoma with a focus of carcinoma at age 47 years. All 3 affected members presented with cutaneous lesions characteristic of MRTES. In affected and asymptomatic members of a 4-generation Italian family (family C) with HNPCC ({120435}), {55:Stella et al. (2007)} identified a 32-kb deletion with identical breakpoints to that found by {4:Barana et al. (2004)} and {60:van der Klift et al. (2005)} in 2 branches of an unrelated 5-generation Italian family (family V+Va); both families and 2 unrelated patients with HNPCC carrying the 32-kb deletion were from the Veneto region of Italy. Haplotype analysis of the 2 families suggested that the MSH2 exon 1-6 deletion is probably a founder mutation. {55:Stella et al. (2007)} noted that skin cancers, including 4 keratoacanthomas, had been reported in 10 of the 19 affected members of family V+Va, and 1 patient from family C had a squamous cell acanthoma. Families V and Va, which had been previously described by {4:Barana et al. (2004)} and {60:van der Klift et al. (2005)} (family It1), respectively, were found to be branches of the same large Italian family described by {55:Stella et al. (2007)}. mutations MSH2, 32-KB DEL, EX1-6 number 23 alternativeNames COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1, INCLUDED clinvarAccessions RCV000001845;;1;;;RCV000023766;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 text In 8 families of Sardinian ancestry with HNPCC1 ({120435}), {6:Borelli et al. (2013)} identified a heterozygous 3,516-bp deletion with a 15-bp insertion in exon 8 of the MSH2 gene. The breakpoints involved a nonrepetitive sequence in intron 7 and an inverted AluSp element in intron 8; the deletion was notated as 1277-1180_1386+2226del3516ins15. Haplotype analysis indicated a founder effect. One of the families was large and included 16 affected individuals spanning 3 generations. The 8 families belong to different villages in southwestern Sardinia. {6:Borelli et al. (2013)} developed a quick test for identification of the deletion. mutations MSH2, 3.5-KB DEL AND 15-BP INS number 24 clinvarAccessions RCV000034315;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 text In 2 families of Sardinian ancestry with HNPCC1 ({120435}), {6:Borelli et al. (2013)} identified a heterozygous 19.28-kb deletion in exon 8 of the MSH2 gene (1276+198_1386+3761del19280). One of the families (family M) was large and included 26 affected individuals in 4 generations. Haplotype analysis indicated a founder effect for the 2 families. The proband from family M was subsequently linked to family M reported by {55:Stella et al. (2007)}, who identified the same exon 8 deletion. {6:Borelli et al. (2013)} developed a quick test for identification of the deletion. mutations MSH2, 19.28-KB DEL number 25 clinvarAccessions RCV000034316;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 dbSnps rs63750704 text In affected members of 16 families from northern Portugal with HNPCC ({120435}), {50:Pinheiro et al. (2013)} identified a heterozygous 2-bp deletion (c.388_389del) in the MSH2 gene. This mutation was found in 16% of 103 probands with HNPCC, and haplotype analysis indicated a relatively recent founder effect in this population. Haplotype analysis of 4 HNPCC1 families with this mutation from Germany, Scotland, England, and Argentina yielded different haplotype backgrounds, supporting the hypothesis that the mutation occurred de novo on multiple occasions. mutations MSH2, 2-BP DEL, NT388 number 26 clinvarAccessions RCV000076592;;3;;;RCV000087058;;1 prefix * titles preferredTitle MutS, E. COLI, HOMOLOG OF, 2; MSH2 textSectionList textSection textSectionTitle Description textSectionContent MSH2 is homologous to the E. coli MutS gene and is involved in DNA mismatch repair (MMR) ({18,17:Fishel et al., 1993, 1994}). Heterozygous mutations in the MSH2 gene result in hereditary nonpolyposis colorectal cancer-1 (HNPCC1; {120435}). Epigenetic silencing of MSH2 caused by deletion of 3-prime regions of the upstream EPCAM gene ({185535}) and intergenic regions results in hereditary nonpolyposis colorectal cancer (HNPCC8; {613244}). Alteration of MSH2 is also involved in Muir-Torre syndrome (MRTES; {158320}) and mismatch repair cancer syndrome (MMRCS; {276300}). textSectionName description textSectionTitle Cloning textSectionContent {18:Fishel et al. (1993)} studied human homologs of the mismatch repair system in E. coli referred to as the MutHLS pathway. The pathway promotes a long patch (approximately 2 kb) excision repair reaction that is dependent on the products of the MutH, MutL, MutS, and MutU genes. Genetic analysis suggested that Saccharomyces cerevisiae has a mismatch repair system similar to the bacterial MutHLS system. The S. cerevisiae pathway has a MutS homolog, MSH2. In both bacteria and S. cerevisiae, mismatch repair plays a role in maintaining the genetic stability of DNA. In S. cerevisiae, Msh2 mutants exhibit increased rates of expansion and contraction of dinucleotide repeat sequences. {18:Fishel et al. (1993)} cloned and characterized a human MutS homolog, MSH2. {32:Leach et al. (1993)} identified the MSH2 gene within the 0.8-Mb interval on chromosome 2p containing the HNPCC1 locus. MSH2 is homologous to a prokaryotic gene, MutS, that participates in mismatch repair. The highest homology is to the yeast Msh2 gene in the helix-turn-helix domain, perhaps responsible for MutS binding to DNA. The yeast and human Msh2 proteins are 77% identical between codons 615 and 788. There are 10 other blocks of similar amino acids distributed throughout the length of the 2 proteins. {21:Genuardi et al. (1998)} reported the existence of alternative splicing in the MSH2 gene. Coupled RT-PCR of various tissue samples from normal individuals and hereditary nonpolyposis colon cancer patients identified MSH2 gene products lacking exons 5, 13, 2-7, and 2-8. The levels of expression varied among different samples. All isoforms were found in 43 to 100% of the mononuclear blood samples, as well as in other tissues. The authors cautioned that knowledge of the existence of multiple alternative splicing events not caused by genomic DNA changes is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis. textSectionName cloning textSectionTitle Gene Function textSectionContent The microsatellite DNA instability that is associated with alteration in the MSH2 gene in hereditary nonpolyposis colon cancer and several forms of sporadic cancer is thought to arise from defective repair of DNA replication errors that create insertion-deletion loop-type (IDL) mismatched nucleotides. {17:Fishel et al. (1994)} showed that purified MSH2 protein efficiently and specifically binds DNA containing IDL mismatches of up to 14 nucleotides. The findings supported a direct role for MSH2 in mutation avoidance and microsatellite stability in human cells. {34:Lishanski et al. (1994)} developed an experimental strategy for detecting heterozygosity in genomic DNA based on preferential binding of E. coli MutS protein to DNA molecules containing mismatched bases. The binding was detected by a gel mobility-shift assay. The approach was tested by using as a model the most commonly occurring mutations within the cystic fibrosis gene (CFTR; {602421}). {48:Pearson et al. (1997)} studied the interaction of the human mismatch repair protein MSH2 with slipped-strand structures formed from a triplet repeat sequence in order to address the possible role of MSH2 in trinucleotide expansion, which is associated with several neurodegenerative diseases such as myotonic dystrophy (DM; {160900}). Genomic clones of the myotonic dystrophy locus containing disease-relevant lengths of (CTG)n(CAG)n triplet repeats were examined. They found that the affinity of MSH2 increased with the length of the repeat sequence. Furthermore, MHS bound preferentially to looped-out CAG repeat sequences, implicating a strand asymmetry in MSH2 recognition. {48:Pearson et al. (1997)} suggested that MSH2 may participate in trinucleotide repeat expansion via its role in repair and/or recombination. All homologs of the MutS proteins contain a highly conserved region of approximately 150 amino acids that encompasses a helix-turn-helix domain associated with an adenine nucleotide and magnesium binding motif, termed Walker-A motif. This part of the molecule has ATPase activity. {22:Gradia et al. (1997}) found that this ATPase activity and the associated adenine nucleotide-binding domain functions to regulate mismatch binding as a molecular switch. The MSH2-MSH6 ({600678}) complex is 'on' (binds mismatched nucleotides) in the ADP-bound form and 'off' in the ATP-bound form. Hydrolysis of ATP results in the recovery of mismatch binding, while ADP-to-ATP exchange results in mismatch dissociation. These results suggested to {22:Gradia et al. (1997)} a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events. {23:Gradia et al. (1999)} showed that ATP-induced release of MSH2-MSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. The authors demonstrated that mismatched DNA provokes ADP-to-ATP exchange, resulting in a conformational transition that converts MSH2-MSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. These results suggested to {23:Gradia et al. (1999)} a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound MSH2-MSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches. Oxidation of G in DNA yields 8-oxo-G (GO), a mutagenic lesion that leads to misincorporation of A opposite GO. In S. cerevisiae, {44:Ni et al. (1999)} found that mutations in the MSH2 or MSH6 genes caused a synergistic increase in mutation rate when in combination with mutations in the OGG1 gene ({601982}), resulting in a 140- to 218-fold increase in the G:C-to-T:A transversion rate. Consistent with this, MSH2-MSH6 complex bound with high affinity and specificity to GO:A mispairs and GO:C basepairs. These data indicated that in S. cerevisiae, MSH2-MSH6-dependent mismatch repair is the major mechanism by which misincorporation of A opposite GO is corrected. {66:Wang et al. (2000)} used immunoprecipitation and mass spectrometry analyses to identify BRCA1 ({113705})-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM ({607585}), BLM ({604610}), MSH2, MSH6, MLH1 ({120436}), the RAD50 ({604040})-MRE1 1 ({600814})-NBS1 ({602667}) complex, and the RFC1 ({102579})-RFC2 ({600404})-RFC4 ({102577}) complex. {66:Wang et al. (2000)} suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. Defective S-phase checkpoint activation results in an inability to downregulate DNA replication following genotoxic insult such as exposure to ionizing radiation. This 'radioresistant DNA synthesis' (RDS) is a phenotypic hallmark of ataxia-telangiectasia, a cancer-predisposing disorder caused by mutations in the ATM gene. The mismatch repair system principally corrects nucleotide mismatches that arise during replication. By studies in cultured cells, {8:Brown et al. (2003)} showed that the mismatch repair system is required for activation of the S-phase checkpoint in response to ionizing radiation. Cells deficient in mismatch repair proteins showed RDS, and restoration of mismatch repair function restored normal S-phase checkpoint function. Catalytic activation of ATM and ATM-mediated phosphorylation of the protein nibrin (NBS1; {602667}), which is mutant in the Nijmegen breakage syndrome ({251260}), occurred independently of mismatch repair. However, ATM-dependent phosphorylation and activation of the checkpoint kinase CHK2 ({604373}) and subsequent degradation of its downstream target, CDC25A ({116947}), was abrogated in cells lacking mismatch repair. Both in vitro and in vivo approaches showed that MSH2 binds CHK2 and that MLH1 associates with ATM. These findings indicated that the mismatch repair complex formed at the sites of DNA damage facilitates the phosphorylation of CHK2 by ATM, and that defects in this mechanism form the molecular basis for the RDS observed in cells deficient in mismatch repair. Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by postreplication mismatch repair (MMR). Inactivation of both mutation-avoidance systems resulting in high mutability and the likelihood of cancer can be caused by mutations (e.g., in the MSH2 gene) and by epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. {26:Jin et al. (2003)} found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicated that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, {26:Jin et al. (2003)} found that cadmium inhibited at least 1 step leading to mismatch removal. Thus, the data showed that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system. {42:McMurray and Tainer (2003)} commented on the direct inhibition of DNA mismatch repair as a molecular mechanism for cadmium toxicity. By immunoprecipitation of human breast cancer cell lines and protein pull-down assays with in vitro translated proteins, {62:Wada-Hiraike et al. (2005)} demonstrated that estrogen receptor-alpha (ESR1; {133430}) interacted with MSH2 in a ligand-dependent manner, whereas estrogen receptor-beta (ESR2; {601663}) and MSH2 interacted in a ligand-independent manner. Both receptors bound MSH2 through its MSH3 ({600887})/MSH6-interaction domain. In a transient expression assay, MSH2 potentiated the transactivation function of ligand-activated ESR1 but not ESR2. {62:Wada-Hiraike et al. (2005)} concluded that MSH2 may be a coactivator of ESR1-dependent gene expression. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent {31:Lamers et al. (2000)} and {45:Obmolova et al. (2000)} independently determined the crystal structure of bacterial MutS binding with substrate DNA. {31:Lamers et al. (2000)} presented the crystal structure at a 2.2-angstrom resolution of MutS from E. coli bound to a G/T mismatch. The 2 MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual basepairing and kinking of the DNA. {31:Lamers et al. (2000)} stated that mutations in human MSH2 that lead to hereditary predisposition for HNPCC can be mapped to this crystal structure. textSectionName biochemicalFeatures textSectionTitle Gene Structure textSectionContent {28:Kolodner et al. (1994)} found that the genomic MSH2 locus covers approximately 73 kb and contains 16 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {18:Fishel et al. (1993)} demonstrated that the MSH2 gene maps to chromosome 2p22-p21 by study of a mapping panel of somatic cell hybrid DNAs using PCR. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Mutations in the MSH2 Gene Causing Colorectal Cancer {18:Fishel et al. (1993)} identified a T-to-C transition in the -6 position of a splice acceptor site in sporadic colon tumors and as a constitutional change in affected members of 2 small families with HNPCC. {32:Leach et al. (1993)} demonstrated the existence of MSH2 germline mutations that substantially altered the predicted gene product and cosegregated with disease in the HNPCC kindreds. Furthermore, they identified specific germline mutations in each of the 2 kindreds that originally established linkage of HNPCC to chromosome 2 (e.g., {609309.0001}) ({49:Peltomaki et al., 1993}). {3:Aquilina et al. (1994)} detected a mismatch binding defect leading to a mutator phenotype in LoVo, a human colorectal carcinoma cell line. {59:Umar et al. (1994)} described a deletion in the MSH2 gene in LoVo cells together with a defect in mismatch repair by LoVo cell extracts. Using denaturing gradient gel electrophoresis (DGGE) to screen for mutations in all 16 exons of the MSH2 gene in 34 unrelated HNPCC kindreds, {71:Wijnen et al. (1995)} found 7 novel pathogenic germline mutations resulting in stop codons, either directly or through frameshifts. Four nonpathogenic variations, including 1 useful polymorphism, were also identified. MSH2 mutations were found in 21% of the families. They could not establish any correlation between the site of the individual mutations and the spectrum of tumor types. {39:Maliaka et al. (1996)} identified 6 different new mutations in the MLH1 ({120436}) and MSH2 genes in Russian and Moldavian HNPCC families. Three of these mutations occurred in CpG dinucleotides and led to a premature stop codon, splicing defect, or an amino acid substitution in evolutionarily conserved residues. Analysis of a compilation of published mutations including the new data suggested to the authors that CpG dinucleotides within the coding regions of the MSH2 and MLH1 genes are hotspots for single basepair substitutions. {15:Ellison et al. (2001)} performed quantitative in vivo DNA mismatch repair (MMR) assays in the yeast S. cerevisiae to determine the functional significance of amino acid replacements in MLH1 and MSH2 genes observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. Three classes of missense codons were found: (i) complete loss of function, i.e., mutations; (ii) variants indistinguishable from wildtype protein, i.e., silent polymorphisms; and (iii) functional variants which supported MMR at reduced efficiency, i.e., efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The authors suggested that differences in the efficiency of DNA MMR may exist between individuals in the human population due to common polymorphisms. {67:Wang et al. (2002)} described a modified multiplex PCR assay effective in detecting large deletions in either the MSH2 or MLH1 gene in HNPCC. {1:Alazzouzi et al. (2005)} studied the allelic distribution of microsatellite repeat bat26 of in peripheral blood lymphocytes of 6 carriers and 4 noncarriers from 2 HNPCC families harboring germline MLH1 and MSH2 mutations, respectively. In noncarriers, there was a gaussian distribution with no bat26 alleles shorter than 21 adenine residues. All 6 MLH1/MSH2 mutation carriers showed unstable bat26 alleles (20 adenine residues or shorter) with an overall frequency of 5.6% (102 of 1814 clones detected). {1:Alazzouzi et al. (2005)} suggested that detection of short unstable bat26 alleles may assist in identifying asymptomatic carriers belonging to families with no detectable MMR gene mutations. {52:Quehenberger et al. (2005)} obtained estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease-causing mutations of the MSH2 and MLH1 genes. Families with known germline mutations of these genes were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for CRC and EC. The MSH2 and MHL1 loci were analyzed jointly as there was no significant difference in risk (p = 0.08). At age 70, CRC risk for men was 26.7% (95% CI, 12.6 to 51.0%) and for women, 22.4% (10.6 to 43.8%); the risk for EC was 31.5% (11.1 to 70.3%). These estimates of risk were considerably lower than ones previously used which did not account for the selection of families. {47:Pagenstecher et al. (2006)} examined 19 variants in the MLH1 and MSH2 genes detected in patients with HNPCC for expression at the RNA level. Ten of the 19 were found to affect splicing, including several variants which were predicted to be missense mutations in exonic sequences (see, e.g., {120436.0024}). The findings suggested that mRNA examination of MLH1 and MSH2 mutations should precede functional tests at the protein levels. Without preselection and regardless of family history, {5:Barnetson et al. (2006)} recruited 870 patients under the age of 55 years soon after they received the diagnosis of colorectal cancer. They studied these patients for germline mutations in DNA mismatch-repair genes MLH1, MSH2, and MSH6 ({600678}) and developed a 2-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. Furthermore, they analyzed 2,938 patient-years of follow-up to determine whether genotype influenced survival. Among the 870 participants, 38 mutations were found: 15 in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6%) and women (3%) differed significantly (P less than 0.04). Survival among carriers was not significantly different from that among noncarriers. Using multiplex ligation-dependent probe amplification, {55:Stella et al. (2007)} analyzed the MSH2 gene in 4 probands from Italian HNPCC families and identified deletions in all 4; 2 carried the same deletion of exons 1-6 ({609309.0023}). Haplotype analysis of the 2 families with the MSH2 1-6 deletion suggested that it might be a founder mutation. Analysis of 23 affected parent-child pairs in the 4 kindreds showed that median age at diagnosis was anticipated in the offspring by 12 years (p = 0.0001). {58:Tournier et al. (2008)} examined potential splicing defects of 56 unclassified variants in the MLH1 gene and 31 in the MSH2 gene that were identified in 82 French patients with Lynch syndrome. The variants comprised 54 missense mutations, 10 synonymous changes, 20 intronic variants, and 3 single-codon deletions. The authors developed an ex vivo splicing assay by inserting PCR-amplified transcripts from patient genomic DNA into a reporter minigene that was transfected into HeLa cells. The ex vivo splicing assay showed that 22 of 85 variant alleles affected splicing, including 4 exonic variants that affected putative splicing regulatory elements. The study provided a tool for evaluating putative pathogenic effects of unclassified variants found in these genes. {57:Tang et al. (2009)} identified pathogenic mutations or deletions in the MLH1 or MSH2 gene in 61 (66%) of 93 Taiwanese families with HNPCC. Eighteen families had MSH2 mutations, including 4 novel point mutations and 7 large deletions, and 1 family harbored MSH2 and MLH1 mutations. {6:Borelli et al. (2013)} identified 5 different heterozygous deletions in exon 8 of the MSH2 gene (see, e.g., {609309.0024}-{609309.0025}) in 13 Italian families with HNPCC1. Ten of the families were of Sardinian origin, and 2 of the mutations showed a founder effect. Epigenetic Silencing of MSH2 in Colorectal Cancer Germline mutations of the DNA mismatch repair (MMR) genes, in particular, the MSH2 and MLH1 ({120436}) genes, cause the most common hereditary cancer, hereditary nonpolyposis colorectal cancer (HNCC) syndrome. These mutations generally take the form of a permanent and stable alteration in DNA, which can be inherited by offspring in a predictable manner. Alternatively, epimutation, which involves a reversible alteration of gene function mediated by cytosine methylation or histone modification without change of the DNA sequence, generally occurs as a somatic event in cancers. The best example is methylation of the MLH1 gene promoter, leading to its transcriptional silencing in sporadic colorectal cancer with mismatch repair deficiency. Although inheritance of epigenetic characteristics had been clearly documented in plants, and to a lesser extent in other animals, evidence supporting its involvement in human disease was limited. {10:Chan et al. (2006)} was among the first to report inheritance, in 3 successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three sibs carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. {10:Chan et al. (2006)} postulated that this mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy. In 4 Dutch and 2 Chinese families with Lynch syndrome, including the family studied by {10:Chan et al. (2006)} with heritable MSH2 promoter methylation, {33:Ligtenberg et al. (2009)} detected deletions of the 3-prime end of the EPCAM gene ({185535}) that led to inactivation of the adjacent MSH2 gene through methylation induction of its promoter in tissues expressing EPCAM. In 4 Dutch families with colorectal cancer showing high microsatellite instability and loss of MSH2 protein, but in which no mutations in MSH2 were found, {33:Ligtenberg et al. (2009)} detected a 5-kb deletion encompassing the 2 most 3-prime exons of the EPCAM gene but leaving the promoter of the MSH2 gene intact ({185535.0005}). In the family of {10:Chan et al. (2006)} and in another unrelated Chinese family, they found a 22.8-kb deletion encompassing the 3-prime end of EPCAM and leaving the MSH2 promoter intact ({185535.0006}). The deletions included the polyadenylation signal of EPCAM and abolished transcriptional termination, leading to transcription read-through into the downstream MSH2 gene. Methylation occurred only in tissues expressing EpCAM among which are the main target tissues in Lynch syndrome. {33:Ligtenberg et al. (2009)} concluded that based on their findings, transcriptional read-through due to deletion of polyadenylation signals may constitute a general mutational mechanism for the inactivation of neighboring genes. Muir-Torre Syndrome {28:Kolodner et al. (1994)} analyzed 2 large HNPCC kindreds exhibiting features of the Muir-Torre syndrome (MRTES; {158320}) and demonstrated that cancer susceptibility was due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family. Linkage of the cancer phenotype to chromosome 2p had been described in these families by {24:Hall et al. (1994)}. {40:Mangold et al. (2004)} screened for mutations in the MSH2 and MLH1 genes in 41 unrelated index patients diagnosed with Muir-Torre syndrome, most of whom were preselected for mismatch repair deficiency in their tumor tissue. Germline mutations were identified in 27 patients (mutation detection rate of 66%). {40:Mangold et al. (2004)} noted that 25 (93%) of the mutations were located in MSH2, in contrast to HNPCC patients without the MRTES phenotype, in whom the proportions of MLH1 and MSH2 mutations are almost equal (p less than 0.001). {40:Mangold et al. (2004)} further noted that 6 (22%) of the mutation carriers did not meet the Bethesda criteria for HNPCC and suggested that sebaceous neoplasm be added to the HNPCC-specific malignancies in the Bethesda guidelines. Mismatch Repair Cancer Syndrome {70:Whiteside et al. (2002)} described a 2-year-old infant with mismatch repair cancer syndrome (MMRCS; {276300}) manifest as T-cell acute lymphoblastic leukemia and multiple cafe-au-lait spots, suggesting neurofibromatosis type I (NF1; {162200}). The child was found to be homozygous for a splice site mutation in the MSH2 gene ({609309.0014}). Both parents were heterozygous for the mutation. Other than cafe-au-lait spots, the infant had no other signs of NF1. There was no family history of either NF1 or cancers indicative of HNPCC. Homozygosity for another DNA mismatch repair gene, MLH1, had been reported in 3 families ({65:Wang et al., 1999}; {54:Ricciardone et al., 1999}; {61:Vilkki et al., 2001}). The homozygous offspring in all of these families were diagnosed with NF1 with no family history of the disorder. Five homozygous children in 2 of the families developed leukemia or lymphoma. {70:Whiteside et al. (2002)} pointed out that more than two-thirds of Msh2 -/- knockout mice succumb to thymic lymphomas. {7:Bougeard et al. (2003)} described 2 sibs, a female who died of mediastinal T-cell lymphoma at the age of 15 months and her brother who died at age 4 years from a temporal glioblastoma. The phenotype was consistent with mismatch repair cancer syndrome. Study of glioblastoma DNA from the boy indicated compound heterozygosity for 2 mutations in the MSH2 gene ({609309.0015}; {609309.0016}). In this family, endometrial carcinoma was the cause of death at age 43 years in an aunt of the mother and at age 59 years in the grandmother of the father. Furthermore, an uncle of the father had died of astrocytoma at age 27 years. Other Cancers {46:Orth et al. (1994)} found that 5 of 10 ovarian tumor cell lines were genetically unstable at most microsatellite loci analyzed. In clones and subclones derived serially from 1 of these cell lines (serous cystadenocarcinoma), a very high proportion of microsatellites distributed in many different regions of the genome changed their size in a mercurial fashion. In 1 ovarian tumor, they identified the source of the genetic instability as a point mutation (arg524 to pro; {609309.0007}) in the MSH2 gene. The patient was a 38-year-old heterozygote for this mutation and her normal tissue carried both mutant and wildtype alleles of the MSH2 gene. However, the wildtype allele was lost at some point early during tumorigenesis so that DNA isolated either from the patients ovarian tumor or from the cell line carried only the mutant MSH2 allele. The genetic instability observed in the tumor and cell line DNA, together with the germline mutation in a mismatch repair gene, suggested that MSH2 is involved in the onset and/or progression in a subset of ovarian cancer. Using specific markers of the mutator phenotype, {14:Duval et al. (2004)} screened a series of 603 human non-Hodgkin lymphomas (NHLs; {605027}) and found 12 microsatellite instability-high (MSI-H) cases (2%). This phenotype was specifically associated with immunodeficiency-related lymphomas being observed in both posttransplant lymphoproliferative disorders and in HIV infection-related lymphomas but not in a large series of NHL arising in the general population. The MSI pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSI-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, {14:Duval et al. (2004)} found that MSI-H immunodeficiency-related lymphomas harbored such genetic alterations in 12 target genes with a putative role in lymphomagenesis. textSectionName molecularGenetics textSectionTitle Cytogenetics textSectionContent {64:Wagner et al. (2002)} identified a paracentric inversion of chromosome 2p that inactivated the MSH2 locus and caused HNPCC. They showed that the centromeric and telomeric breakpoints of the paracentric inversion mapped within intron 7 of the MSH2 gene and to a contig 10 Mb 3-prime of MSH2, respectively. Northern and Western blot analyses showed that expression of MSH2 was abolished. textSectionName cytogenetics textSectionTitle Animal Model textSectionContent To investigate the role of the MSH2 gene in genome stability and tumorigenesis, {13:de Wind et al. (1995)} generated cells and mice deficient for the gene. Msh2-deficient mouse embryonic stem cell lines were found to have lost mismatch binding and acquired microsatellite instability, a mutator phenotype, and tolerance to methylation agents. Moreover, in these cells, homologous recombination had lost dependence on complete identity between interacting DNA sequences, suggesting that Msh2 is involved in safeguarding the genome from promiscuous recombination. MSH2-deficient mice displayed no major abnormalities, but a significant fraction developed lymphomas at an early age. {53:Reitmair et al. (1995)} described a mouse strain homozygous for a 'knockout' mutation at the MSH2 locus. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio, and bred through at least 2 generations. Starting at 2 months of age, homozygous MSH2-deficient mice began to develop lymphoid tumors with high frequency that contained microsatellite instabilities. These data established a direct link between MSH2 deficiency and the pathogenesis of cancer. Mice carrying a targeted germline disruption of the MSH2 gene are viable and susceptible to lymphoid tumors; however, defects in this gene had not been identified in human lymphomas. To determine if the lymphomas these mice develop are related to a particular subtype of human lymphoma, {37:Lowsky et al. (1997)} evaluated 20 clinically ill homozygous MSH2 -/- mice ranging in age from 2 to 13 months. The murine tumors comprised a single histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembling human precursor T-cell lymphoblastic lymphoma (LBL). Evaluation of the expression of 3 T-cell malignancy-associated genes showed that rhombotin-2 (RBTN2; {180385}), TAL1 ({187040}), and HOX11 ({186770}) were expressed in 100, 40, and 0% of the murine tumors, respectively. The MSH2 -/- murine model of precursor T-cell LBL was substantiated by the finding of a newly identical expression pattern of RBTM2, TAL1, and HOX11 in 10 well-characterized cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was established by sequence analysis of exon 13 of human MSH2, which revealed coding region mutations in 2 of 10 cases. The findings of {37:Lowsky et al. (1997)} implicated defects in the mismatch repair system with the aberrant expression of T-cell specific protooncogenes and defined a new pathway of human lymphomagenesis. Chronic oxidative stress may play a critical role in the pathogenesis of many human cancers. {12:DeWeese et al. (1998)} reported that mouse embryonic stem (ES) cells from mice carrying either 1 or 2 disrupted Msh2 alleles displayed an increased survival following protracted exposures to low-level ionizing radiation as compared with wildtype ES cells. The increases in survival exhibited by ES cells deficient in DNA mismatch repair appeared to have resulted from a failure to execute cell death (apoptosis) efficiently in response to radiation exposure. For each of the ES cell types, prolonged low-level radiation treatment generated oxidative genome damage that manifested as an accumulation of oxidized bases in genomic DNA. However, ES cells from Msh2 +/- and Msh2 -/- mice accumulated more oxidized bases as a consequence of low-level radiation exposure than did ES cells from Msh2 +/+ mice. The propensity for normal cells with mismatch repair enzyme deficiencies, including cells heterozygous for inactivating mismatch repair enzyme gene mutations, to survive promutagenic genome insults accompanying stresses may contribute to the increased cancer risk characteristic of the hereditary nonpolyposis colorectal cancer syndrome. Somatic instability of expanded huntingtin (HTT; {613004}) CAG repeats that encode the polyglutamine tract in mutant huntingtin has been implicated in the striatal selectivity of Huntington disease (HD; {143100}) pathology. {69:Wheeler et al. (2003)} tested whether a genetic background deficient in Msh2 would eliminate the unstable behavior of the CAG array in Hdh(Q111) mice. Analyses of Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+):Msh2(-/-) progeny revealed that, while inherited instability involved Msh2-dependent and -independent mechanisms, lack of Msh2 was sufficient to abrogate progressive HD CAG repeat expansion in striatum. The absence of Msh2 also eliminated striatal mutant huntingtin with somatically expanded glutamine tracts and caused an approximately 5-month delay in nuclear mutant protein accumulation, but did not alter the striatal specificity of this early phenotype. In HD(+/-)/Msh2(+/+) and HD(+/-)/Msh2(-/-) mice, {29:Kovtun et al. (2004)} showed that long CAG repeats were shortened during somatic replication early in embryonic development. Deletions arose during replication, did not depend on the presence of Msh2, and were largely restricted to early development. In contrast, expansions depended on strand break repair, required the presence of Msh2, and occurred later in development. {29:Kovtun et al. (2004)} hypothesized that deletions in early development may serve to safeguard the genome and protect against expansion of disease-range repeats during parent-offspring transmission. textSectionName animalModel geneMapExists true editHistory carol : 02/18/2014 mcolton : 2/18/2014 ckniffin : 2/17/2014 carol : 3/26/2013 ckniffin : 3/20/2013 terry : 9/14/2012 terry : 8/31/2012 carol : 7/20/2011 wwang : 5/11/2011 wwang : 1/4/2011 ckniffin : 12/3/2010 carol : 11/4/2010 alopez : 2/5/2010 alopez : 2/4/2010 wwang : 9/15/2009 wwang : 9/15/2009 ckniffin : 8/28/2009 carol : 6/3/2009 wwang : 2/25/2009 ckniffin : 2/18/2009 wwang : 1/29/2008 terry : 1/18/2008 ckniffin : 1/16/2008 carol : 1/15/2008 ckniffin : 1/7/2008 wwang : 11/28/2007 terry : 11/8/2007 wwang : 6/1/2007 terry : 5/21/2007 alopez : 11/1/2006 alopez : 10/30/2006 terry : 10/26/2006 alopez : 6/16/2006 wwang : 5/17/2006 ckniffin : 5/17/2006 alopez : 3/13/2006 terry : 3/7/2006 wwang : 2/13/2006 ckniffin : 2/8/2006 terry : 2/3/2006 wwang : 12/1/2005 wwang : 11/28/2005 wwang : 11/28/2005 terry : 11/9/2005 carol : 8/31/2005 wwang : 7/13/2005 wwang : 7/6/2005 mgross : 4/15/2005 mgross : 4/14/2005 mgross : 4/14/2005 dateCreated Thu, 14 Apr 2005 03:00:00 EDT creationDate Victor A. McKusick : 4/14/2005 epochUpdated 1392710400 dateUpdated Tue, 18 Feb 2014 03:00:00 EST referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15563510 publisherName HighWire Press title Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. mimNumber 609309 referenceNumber 1 publisherAbbreviation HighWire pubmedID 15563510 source Hum. Molec. Genet. 14: 235-239, 2005. authors Alazzouzi, H., Domingo, E., Gonzalez, S., Blanco, I., Armengol, M., Espin, E., Plaja, A., Schwartz, S., Capella, G., Schwartz, S., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu source Edmonton, Alberta, Canada 4/11/2002. mimNumber 609309 authors Andrew, S. title Personal Communication. referenceNumber 2 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8090742 publisherName HighWire Press title A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. mimNumber 609309 referenceNumber 3 publisherAbbreviation HighWire pubmedID 8090742 source Proc. Nat. Acad. Sci. 91: 8905-8909, 1994. authors Aquilina, G., Hess, P., Branch, P., MacGeoch, C., Casciano, I., Karran, P., Bignami, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.20523 publisherName John Wiley & Sons, Inc. title Spectrum of genetic alterations in Muir-Torre syndrome is the same as in HNPCC. (Letter) mimNumber 609309 referenceNumber 4 publisherAbbreviation Wiley pubmedID 14994245 source Am. J. Med. Genet. 125A: 318-319, 2004. authors Barana, D., Cetto, G. L., Oliani, C., van der Klift, H., Wijnen, J., Fodde, R., Dalla Longa, E., Radice, P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa053493?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. mimNumber 609309 referenceNumber 5 publisherAbbreviation ATYPON pubmedID 16807412 source New Eng. J. Med. 354: 2751-2763, 2006. authors Barnetson, R. A., Tenesa, A., Farrington, S. M., Nicholl, I. D., Cetnarskyj, R., Porteous, M. E., Campbell, H., Dunlop, M. G. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1038/ejhg.2012.150 publisherName Nature Publishing Group title A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin. mimNumber 609309 referenceNumber 6 publisherAbbreviation NPG pubmedID 22781090 source Europ. J. Hum. Genet. 21: 154-161, 2013. authors Borelli, I., Barberis, M. A., Spina, F., Casalis Cavalchini, G. C., Vivanet, C., Balestrino, L., Micheletti, M., Allavena, A., Sala, P., Carcassi, C., Pasini, B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60521-7 publisherName Elsevier Science title Early-onset brain tumor and lymphoma in MSH2-deficient children. (Letter) mimNumber 609309 referenceNumber 7 publisherAbbreviation ES pubmedID 12549480 source Am. J. Hum. Genet. 72: 213-216, 2003. authors Bougeard, G., Charbonnier, F., Moerman, A., Martin, C., Ruchoux, M. M., Drouot, N., Frebourg, T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng1052 publisherName Nature Publishing Group title The mismatch repair system is required for S-phase checkpoint activation. mimNumber 609309 referenceNumber 8 publisherAbbreviation NPG pubmedID 12447371 source Nature Genet. 33: 80-84, 2003. authors Brown, K. D., Rathi, A., Kamath, R., Beardsley, D. I., Zhan, Q., Mannino, J. L., Baskaran, R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)64367-5 publisherName Elsevier Science title MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population. mimNumber 609309 referenceNumber 9 publisherAbbreviation ES pubmedID 15042510 source Am. J. Hum. Genet. 74: 1035-1042, 2004. authors Chan, T. L., Chan, Y. W., Ho, J. W. C., Chan, C., Chan, A. S. Y., Chan, E., Lam, P. W. Y., Tse, C. W., Lee, K. C., Lau, C. W., Gwi, E., Leung, S. Y., Yuen, S. T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng1866 publisherName Nature Publishing Group title Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. mimNumber 609309 referenceNumber 10 publisherAbbreviation NPG pubmedID 16951683 source Nature Genet. 38: 1178-1183, 2006. authors Chan, T. L., Yuen, S. T., Kong, C. K., Chan, Y. W., Chan, A. S. Y., Ng, W. F., Tsui, W. Y., Lo, M. W. S., Tam, W. Y., Li, V. S. W., Leung, S. Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10978353 publisherName HighWire Press title Recurrent germline mutation in MSH2 arises frequently de novo. mimNumber 609309 referenceNumber 11 publisherAbbreviation HighWire pubmedID 10978353 source J. Med. Genet. 37: 646-652, 2000. authors Desai, D. C., Lockman, J. C., Chadwick, R. B., Gao, X., Percesepe, A., Evans, D. G. R., Miyaki, M., Yuen, S. T., Radice, P., Maher, E. R., Wright, F. A., de la Chapelle, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9751765 publisherName HighWire Press title Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiation. mimNumber 609309 referenceNumber 12 publisherAbbreviation HighWire pubmedID 9751765 source Proc. Nat. Acad. Sci. 95: 11915-11920, 1998. authors DeWeese, T. L., Shipman, J. M., Larrier, N. A., Buckley, N. M., Kidd, L. R., Groopman, J. D., Cutler, R. G., te Riele, H., Nelson, W. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(95)90319-4 publisherName Elsevier Science title Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. mimNumber 609309 referenceNumber 13 publisherAbbreviation ES pubmedID 7628020 source Cell 82: 321-330, 1995. authors de Wind, N., Dekker, M., Berns, A., Radman, M., te Riele, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15047891 publisherName HighWire Press title The mutator pathway is a feature of immunodeficiency-related lymphomas. mimNumber 609309 referenceNumber 14 publisherAbbreviation HighWire pubmedID 15047891 source Proc. Nat. Acad. Sci. 101: 5002-5007, 2004. authors Duval, A., Raphael, M., Brennetot, C., Poirel, H., Buhard, O., Aubry, A., Martin, A., Krimi, A., Leblond, V., Gabarre, J., Davi, F., Charlotte, F., {and 15 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11555625 publisherName HighWire Press title Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. mimNumber 609309 referenceNumber 15 publisherAbbreviation HighWire pubmedID 11555625 source Hum. Molec. Genet. 10: 1889-1900, 2001. authors Ellison, A. R., Lofing, J., Bitter, G. A. pubmedImages false publisherUrl http://highwire.stanford.edu title Muir-Torre syndrome: clinical features and molecular genetic analysis. mimNumber 609309 referenceNumber 16 pubmedID 9217825 source Brit. J. Derm. 136: 913-917, 1997. authors Esche, C., Kruse, R., Lamberti, C., Friedl, W., Propping, P., Lehmann, P., Ruzicka, T. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=7973733 publisherName HighWire Press title Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. mimNumber 609309 referenceNumber 17 publisherAbbreviation HighWire pubmedID 7973733 source Science 266: 1403-1405, 1994. authors Fishel, R., Ewel, A., Lee, S., Lescoe, M. K., Griffith, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(93)90546-3 publisherName Elsevier Science title The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. mimNumber 609309 referenceNumber 18 publisherAbbreviation ES pubmedID 8252616 source Cell 75: 1027-1038, 1993. Note: Erratum: Cell 77: following 166, 1994. authors Fishel, R., Lescoe, M. K., Rao, M. R. S., Copeland, N. G., Jenkins, N. A., Garber, J., Kane, M., Kolodner, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60860-X publisherName Elsevier Science title The founder mutation MSH2*1906G-C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. mimNumber 609309 referenceNumber 19 publisherAbbreviation ES pubmedID 12454801 source Am. J. Hum. Genet. 71: 1395-1412, 2002. authors Foulkes, W. D., Thiffault, I., Gruber, S. B., Horwitz, M., Hamel, N., Lee, C., Shia, J., Markowitz, A., Figer, A., Friedman, E., Farber, D., Greenwood, C. M. T., {and 21 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10051005 publisherName HighWire Press title A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. mimNumber 609309 referenceNumber 20 publisherAbbreviation HighWire pubmedID 10051005 source J. Med. Genet. 36: 97-102, 1999. authors Froggatt, N. J., Green, J., Brassett, C., Evans, D. G. R., Bishop, D. T., Kolodner, R., Maher, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/8102001/81020015.htm publisherName Springer title Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. mimNumber 609309 referenceNumber 21 publisherAbbreviation Springer pubmedID 9490293 source Hum. Genet. 102: 15-20, 1998. authors Genuardi, M., Viel, A., Bonora, D., Capozzi, E., Bellacosa, A., Leonardi, F., Valle, R., Ventura, A., Pedroni, M., Boiocchi, M., Neri, G. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80490-0 publisherName Elsevier Science title The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. mimNumber 609309 referenceNumber 22 publisherAbbreviation ES pubmedID 9428522 source Cell 91: 995-1005, 1997. authors Gradia, S., Acharya, S., Fishel, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)80316-0 publisherName Elsevier Science title hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. mimNumber 609309 referenceNumber 23 publisherAbbreviation ES pubmedID 10078208 source Molec. Cell 3: 255-261, 1999. authors Gradia, S., Subramanian, D., Wilson, T., Acharya, S., Makhov, A., Griffith, J., Fishel, R. pubmedImages false publisherUrl http://www.elsevier.com/ title Genetic linkage in Muir-Torre syndrome to the same chromosomal site as cancer family syndrome. mimNumber 609309 referenceNumber 24 pubmedID 8155392 source Europ. J. Cancer 30A: 180-182, 1994. authors Hall, N. R., Murday, V. A., Chapman, P., Williams, M. A., Burn, J., Finan, P. J., Bishop, D. T. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1996)7:4<327::AID-HUMU6>3.0.CO;2-5 publisherName John Wiley & Sons, Inc. title Mutation of the hMSH2 gene in two families with hereditary nonpolyposis colorectal cancer. mimNumber 609309 referenceNumber 25 publisherAbbreviation Wiley pubmedID 8723682 source Hum. Mutat. 7: 327-333, 1996. authors Jeon, H. M., Lynch, P. M., Howard, L., Ajani, J., Levin, B., Frazier, M. L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng1172 publisherName Nature Publishing Group title Cadmium is a mutagen that acts by inhibiting mismatch repair. mimNumber 609309 referenceNumber 26 publisherAbbreviation NPG pubmedID 12796780 source Nature Genet. 34: 326-329, 2003. authors Jin, Y. H., Clark, A. B., Slebos, R. J. C., Al-Refai, H., Taylor, J. A., Kunkel, T. A., Resnick, M. A., Gordenin, D. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ejhg.2008.153 publisherName Nature Publishing Group title Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A-G of MSH2. mimNumber 609309 referenceNumber 27 publisherAbbreviation NPG pubmedID 18781192 source Europ. J. Hum. Genet. 17: 159-164, 2009. authors Kets, C. M., Hoogerbrugge, N., van Krieken, J. H. J. M., Goossens, M., Brunner, H. G., Ligtenberg, M. J. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888754384716612 publisherName Elsevier Science title Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. mimNumber 609309 referenceNumber 28 publisherAbbreviation ES pubmedID 7713503 source Genomics 24: 516-526, 1994. Note: Erratum: Genomics 28: 613 only, 1995. authors Kolodner, R. D., Hall, N. R., Lipford, J., Kane, M. F., Rao, M. R. S., Morrison, P., Wirth, L., Finan, P. J., Burn, J., Chapman, P., Earabino, C., Merchant, E., Bishops, D. T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15496421 publisherName HighWire Press title Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations. mimNumber 609309 referenceNumber 29 publisherAbbreviation HighWire pubmedID 15496421 source Hum. Molec. Genet. 13: 3057-3068, 2004. authors Kovtun, I. V., Thornhill, A. R., McMurray, C. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2006&volume=69&issue=1&spage=40 publisherName Blackwell Publishing title Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). mimNumber 609309 referenceNumber 30 publisherAbbreviation Blackwell pubmedID 16451135 source Clin. Genet. 69: 40-47, 2006. authors Kurzawski, G., Suchy, J., Lener, M., Klujszo-Grabowska, E., Kladny, J., Safranow, K., Jakubowska, K., Jakubowska, A., Huzarski, T., Byrski, T., Debniak, T., Cybulski, C., {and 30 others} pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1038/35037523 publisherName Nature Publishing Group title The crystal structure of DNA mismatch repair protein MutS binding to a G/T mismatch. mimNumber 609309 referenceNumber 31 publisherAbbreviation NPG pubmedID 11048711 source Nature 407: 711-717, 2000. authors Lamers, M. H., Perrakis, A., Enzlin, J. H., Winterwerp, H. H. K., de Wind, N., Sixma, T. K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(93)90330-S publisherName Elsevier Science title Mutations of a MutS homolog in hereditary non-polyposis colorectal cancer. mimNumber 609309 referenceNumber 32 publisherAbbreviation ES pubmedID 8261515 source Cell 75: 1215-1225, 1993. authors Leach, F. S., Nicolaides, N. C., Papadopoulos, N., Liu, B., Jen, J., Parsons, R., Peltomaki, P., Sistonen, P., Aaltonen, L. A., Nystrom-Lahti, M., Guan, X.-Y., Zhang, J., {and 23 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng.283 publisherName Nature Publishing Group title Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3-prime exons of TACSTD1. mimNumber 609309 referenceNumber 33 publisherAbbreviation NPG pubmedID 19098912 source Nature Genet. 41: 112-117, 2009. authors Ligtenberg, M. J. L., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., Lee, T. Y. H., Bodmer, D., Hoenselaar, E., Hendriks-Cornelissen, S. J. B., Tsui, W. Y., Kong, C. K., Brunner, H. G., Geurts van Kessel, A., Yuen, S. T., van Krieken, J. H. J. M., Leung, S. Y., Hoogerbrugge, N. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7511817 publisherName HighWire Press title Mutation detection by mismatch binding protein, MutS, in amplified DNA: application to the cystic fibrosis gene. mimNumber 609309 referenceNumber 34 publisherAbbreviation HighWire pubmedID 7511817 source Proc. Nat. Acad. Sci. 91: 2674-2678, 1994. authors Lishanski, A., Ostrander, E. A., Rine, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=8062247 publisherName HighWire Press title hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. mimNumber 609309 referenceNumber 35 publisherAbbreviation HighWire pubmedID 8062247 source Cancer Res. 54: 4590-4594, 1994. authors Liu, B., Parsons, R. E., Hamilton, S. R., Petersen, G. M., Lynch, H. T., Watson, P., Markowitz, S., Willson, J. K. V., Green, J., de la Chapelle, A., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0959804998002172 publisherName Elsevier Science title MSH2 codon 322 gly to asp seems not to confer an increased risk for colorectal cancer susceptibility. (Letter) mimNumber 609309 referenceNumber 36 publisherAbbreviation ES pubmedID 10023327 source Europ. J. Cancer 34: 1981 only, 1998. authors Liu, T., Stathopoulos, P., Lindblom, P., Rubio, C., Wasteson Arver, B., Iselius, L., Holmberg, E., Gronberg, H., Lindblom, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9116269 publisherName HighWire Press title Defects of the mismatch repair gene MSH2 are implicated in the development of murine and human lymphoblastic lymphomas and are associated with the aberrant expression of rhombotin-2 (Lmo-2) and Tal-1 (SCL). mimNumber 609309 referenceNumber 37 publisherAbbreviation HighWire pubmedID 9116269 source Blood 89: 2276-2282, 1997. authors Lowsky, R., DeCoteau, J. F., Reitmair, A. H., Ichinohasama, R., Dong, W.-F., Xu, Y., Mak, T. W., Kadin, M. E., Minden, M. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=14871915 publisherName HighWire Press title A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. mimNumber 609309 referenceNumber 38 publisherAbbreviation HighWire pubmedID 14871915 source JAMA 291: 718-724, 2004. authors Lynch, H. T., Coronel, S. M., Okimoto, R., Hampel, H., Sweet, K., Lynch, J. F., Barrows, A., Wijnen, J., van der Klift, H., Franken, P., Wagner, A., Fodde, R., de la Chapelle, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/6097002/60970251.htm publisherName Springer title CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. mimNumber 609309 referenceNumber 39 publisherAbbreviation Springer pubmedID 8566964 source Hum. Genet. 97: 251-255, 1996. authors Maliaka, Y. K., Chudina, A. P., Belev, N. F., Alday, P., Bochkov, N. P., Buerstedde, J.-M. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15235030 publisherName HighWire Press title A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. (Letter) mimNumber 609309 referenceNumber 40 publisherAbbreviation HighWire pubmedID 15235030 source J. Med. Genet. 41: 567-572, 2004. authors Mangold, E., Pagenstecher, C., Leister, M., Mathiak, M., Rutten, A., Friedl, W., Propping, P., Ruzicka, T., Kruse, R. pubmedImages false publisherUrl http://highwire.stanford.edu title Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. mimNumber 609309 referenceNumber 41 pubmedID 7874129 source Hum. Molec. Genet. 3: 2067-2069, 1994. authors Mary, J.-L., Bishop, T., Kolodner, R., Lipford, J. R., Kane, M., Weber, W., Torhorst, J., Muller, H., Spycher, M., Scott, R. J. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0703-239 publisherName Nature Publishing Group title Cancer, cadmium and genome integrity. mimNumber 609309 referenceNumber 42 publisherAbbreviation NPG pubmedID 12833042 source Nature Genet. 34: 239-241, 2003. authors McMurray, C. T., Tainer, J. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.31070 publisherName John Wiley & Sons, Inc. title A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. mimNumber 609309 referenceNumber 43 publisherAbbreviation Wiley pubmedID 16372347 source Am. J. Med. Genet. 140A: 195-199, 2006. authors Muller, A., Schackert, H. K., Lange, B., Ruschoff, J., Fuzesi, L., Willert, J., Burfeind, P., Shah, P., Becker, H., Epplen, J. T., Stemmler, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)80346-9 publisherName Elsevier Science title MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. mimNumber 609309 referenceNumber 44 publisherAbbreviation ES pubmedID 10518225 source Molec. Cell 4: 439-444, 1999. authors Ni, T. T., Marsischky, G. T., Kolodner, R. D. pubmedImages false publisherUrl http://www.elsevier.com/ source Nature 4 07: 703-710, 2000. mimNumber 609309 authors Obmolova, G., Ban, C., Hsieh, P., Yang, W. title Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. referenceNumber 45 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7937795 publisherName HighWire Press title Genetic instability in human ovarian cancer cell lines. mimNumber 609309 referenceNumber 46 publisherAbbreviation HighWire pubmedID 7937795 source Proc. Nat. Acad. Sci. 91: 9495-9499, 1994. authors Orth, K., Hung, J., Gazdar, A., Bowcock, A., Mathis, J. M., Sambrook, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1007/s00439-005-0107-8 publisherName Springer title Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. mimNumber 609309 referenceNumber 47 publisherAbbreviation Springer pubmedID 16341550 source Hum. Genet. 119: 9-22, 2006. authors Pagenstecher, C., Wehner, M., Friedl, W., Rahner, N., Aretz, S., Friedrichs, N., Sengteller, M., Henn, W., Buettner, R., Propping, P., Mangold, E. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9215683 publisherName HighWire Press title Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. mimNumber 609309 referenceNumber 48 publisherAbbreviation HighWire pubmedID 9215683 source Hum. Molec. Genet. 6: 1117-1123, 1997. authors Pearson, C. E., Ewel, A., Acharya, S., Fishel, R. A., Sinden, R. R. pubmedImages false publisherUrl http://highwire.stanford.edu source Scienc e 260: 810-812, 1993. mimNumber 609309 authors Peltomaki, P., Aaltonen, L. A., Sistonen, P., Pylkkanen, L., Mecklin, J.-P., Jarvinen, H., Green, J. S., Jass, J. R., Weber, J. L., Leach, F. S., Petersen, G. M., Hamilton, S. R., de la Chapelle, A., Vogelstein, B. title Genetic mapping of a locus predisposing to human colorectal cancer. referenceNumber 49 articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2013&volume=84&issue=3&spage=244 publisherName Blackwell Publishing title The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families. mimNumber 609309 referenceNumber 50 publisherAbbreviation Blackwell pubmedID 23170986 source Clin. Genet. 84: 244-250, 2013. authors Pinheiro, M., Pinto, C., Peixoto, A., Veiga, I., Mesquita, B., Henrique, R., Lopes, P., Sousa, O., Fragoso, M., Dias, L. M., Baptista, M., Marinho, C., Mangold, E., Vaccaro, C., Evans, D. G., Farrington, S., Dunlop, M. G., Teixeira, M. R. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2003&volume=63&issue=3&spage=215 publisherName Blackwell Publishing title Identification of a deletion in the mismatch repair gene, MSH2, using mouse-human cell hybrids monosomal for chromosome 2. mimNumber 609309 referenceNumber 51 publisherAbbreviation Blackwell pubmedID 12694232 source Clin. Genet. 63: 215-218, 2003. authors Pyatt, R. E., Nakagawa, H., Hampel, H., Sedra, M., Fuchik, M. B., Comeras, I., de la Chapelle, A., Prior, T. W. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15937084 publisherName HighWire Press title Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. mimNumber 609309 referenceNumber 52 publisherAbbreviation HighWire pubmedID 15937084 source J. Med. Genet. 42: 491-496, 2005. authors Quehenberger, F., Vasen, H. F. A., van Houwelingen, H. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0995-64 publisherName Nature Publishing Group title MSH2 deficient mice are viable and susceptible to lymphoid tumours. mimNumber 609309 referenceNumber 53 publisherAbbreviation NPG pubmedID 7550317 source Nature Genet. 11: 64-70, 1995. authors Reitmair, A. H., Schmits, R., Ewel, A., Bapat, B., Redston, M., Mitri, A., Waterhouse, P., Mittrucker, H.-W., Wakeham, A., Liu, B., Thomason, A., Griesser, H., Gallinger, S., Ballhausen, W. G., Fishel, R., Mak, T. W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9927033 publisherName HighWire Press title Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. mimNumber 609309 referenceNumber 54 publisherAbbreviation HighWire pubmedID 9927033 source Cancer Res. 59: 290-293, 1999. authors Ricciardone, M. D., Ozcelik, T., Cevher, B., Ozdag, H., Tuncer, M., Gurgey, A., Uzunalimoglu, O., Cetinkaya, H., Tanyeli, A., Erken, E., Ozturk, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2007&volume=71&issue=2&spage=130 publisherName Blackwell Publishing title Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. mimNumber 609309 referenceNumber 55 publisherAbbreviation Blackwell pubmedID 17250661 source Clin. Genet. 71: 130-139, 2007. authors Stella, A., Surdo, N. C., Lastella, P., Barana, D., Oliani, C., Tibiletti, M. G., Viel, A., Natale, C., Piepoli, A., Marra, G., Guanti, G. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16199548 publisherName HighWire Press title The HNPCC associated MSH2*1906G-C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population. mimNumber 609309 referenceNumber 56 publisherAbbreviation HighWire pubmedID 16199548 source J. Med. Genet. 42: 766-768, 2005. authors Sun, S., Greenwood, C. M. T., Thiffault, I., Hamel, N., Chong, G., Foulkes, W. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2009&volume=75&issue=4&spage=334 publisherName Blackwell Publishing title Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. mimNumber 609309 referenceNumber 57 publisherAbbreviation Blackwell pubmedID 19419416 source Clin. Genet. 75: 334-345, 2009. authors Tang, R., Hsiung, C., Wang, J.-Y., Lai, C.-H., Chien, H.-T., Chiu, L.-L., Liu, C.-T., Chen, H.-H., Wang, H.-M., Chen, S.-X., Hsieh, L.-L., {the TCOG HNPCC Consortium} pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/humu.20796 publisherName John Wiley & Sons, Inc. title A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. mimNumber 609309 referenceNumber 58 publisherAbbreviation Wiley pubmedID 18561205 source Hum. Mutat. 29: 1412-1424, 2008. authors Tournier, I., Vezain, M., Martins, A., Charbonnier, F., Baert-Desurmont, S., Olschwang, S., Wang, Q., Buisine, M. P., Soret, J., Tazi, J., Frebourg, T., Tosi, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8182040 publisherName HighWire Press title Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. mimNumber 609309 referenceNumber 59 publisherAbbreviation HighWire pubmedID 8182040 source J. Biol. Chem. 269: 14367-14370, 1994. authors Umar, A., Boyer, J. C., Thomas, D. C., Nguyen, D. C., Risinger, J. I., Boyd, J., Ionov, Y., Perucho, M., Kunkel, T. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/gcc.20219 publisherName John Wiley & Sons, Inc. title Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). mimNumber 609309 referenceNumber 60 publisherAbbreviation Wiley pubmedID 15942939 source Genes Chromosomes Cancer 44: 123-138, 2005. authors van der Klift, H., Wijnen, J., Wagner, A., Verkuilen, P., Tops, C., Otway, R., Kohonen-Corish, M., Vasen, H., Oliani, C., Barana, D., Moller, P., DeLozier-Blanchet, C., Hutter, P., Foulkes, W., Lynch, H., Burn, J., Moslein, G., Fodde, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11389087 publisherName HighWire Press title Extensive somatic microsatellite mutations in normal human tissue. mimNumber 609309 referenceNumber 61 publisherAbbreviation HighWire pubmedID 11389087 source Cancer Res. 61: 4541-4544, 2001. authors Vilkki, S., Tsao, J.-L., Loukola, A., Poyhonen, M., Vierimaa, O., Herva, R., Aaltonen, L. A., Shibata, D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.bjc.6602614 publisherName Nature Publishing Group title The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor-alpha. mimNumber 609309 referenceNumber 62 publisherAbbreviation NPG pubmedID 15886699 source Brit. J. Cancer 92: 2286-2291, 2005. authors Wada-Hiraike, O., Yano, T., Nei, T., Matsumoto, Y., Nagasaka, K., Takizawa, S., Oishi, H., Arimoto, T., Nakagawa, S., Yasugi, T., Kato, S., Taketani, Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60638-7 publisherName Elsevier Science title Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. mimNumber 609309 referenceNumber 63 publisherAbbreviation ES pubmedID 12658575 source Am. J. Hum. Genet. 72: 1088-1100, 2003. authors Wagner, A., Barrows, A., Wijnen, J., van der Klift, H., Franken, P. F., Verkuijlen, P., Nakagawa, H., Geugien, M., Jaghmohan-Changur, S., Breukel, C., Meijers-Heijboer, H., Morreau, H., {and 10 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/gcc.10094 publisherName John Wiley & Sons, Inc. title A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. mimNumber 609309 referenceNumber 64 publisherAbbreviation Wiley pubmedID 12203789 source Genes Chromosomes Cancer 35: 49-57, 2002. authors Wagner, A., van der Klift, H., Franken, P., Wijnen, J., Breukel, C., Bezrookove, V., Smits, R., Kinarsky, Y., Barrows, A., Franklin, B., Lynch, J., Lynch, H., Fodde, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9927034 publisherName HighWire Press title Neurofibromatosis and early onset of cancers in hMLH1-deficient children. mimNumber 609309 referenceNumber 65 publisherAbbreviation HighWire pubmedID 9927034 source Cancer Res. 59: 294-297, 1999. authors Wang, Q., Lasset, C., Desseigne, F., Frappaz, D., Bergeron, C., Navarro, C., Ruano, E., Puisieux, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=10783165 publisherName HighWire Press title BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. mimNumber 609309 referenceNumber 66 publisherAbbreviation HighWire pubmedID 10783165 source Genes Dev. 14: 927-939, 2000. authors Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10042 publisherName John Wiley & Sons, Inc. title A modified multiplex PCR assay for detection of large deletions in MSH2 or MLH1. mimNumber 609309 referenceNumber 67 publisherAbbreviation Wiley pubmedID 11857745 source Hum. Mutat. 19: 279-286, 2002. authors Wang, Y., Friedl, W., Sengteller, M., Jungck, M., Filges, I., Propping, P., Mangold, E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source Arch. Intern. Med. 12: 546-555, 1913. mimNumber 609309 authors Warthin, A. S. title Heredity with reference to carcinoma. referenceNumber 68 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12554681 publisherName HighWire Press title Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. mimNumber 609309 referenceNumber 69 publisherAbbreviation HighWire pubmedID 12554681 source Hum. Molec. Genet. 12: 273-281, 2003. authors Wheeler, V. C., Lebel, L.-A., Vrbanac, V., Teed, A., te Riele, H., MacDonald, M. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11809679 publisherName HighWire Press title A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. mimNumber 609309 referenceNumber 70 publisherAbbreviation HighWire pubmedID 11809679 source Cancer Res. 62: 359-362, 2002. authors Whiteside, D., McLeod, R., Graham, G., Steckley, J. L., Booth, K., Somerville, M. J., Andrew, S. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. mimNumber 609309 referenceNumber 71 pubmedID 7726159 source Am. J. Hum. Genet. 56: 1060-1066, 1995. authors Wijnen, J., Vasen, H., Khan, P. M., Menko, F. H., van der Klift, H., van Leeuwen, C., van den Broek, M., van Leeuwen-Cornelisse, I., Nagengast, F., Meijers-Heijboer, A., Lindhout, D., Griffioen, G., Cats, A., Kleibeuker, J., Varesco, L., Bertario, L., Bisgaard, M. L., Mohr, J., Fodde, R. pubmedImages false articleUrl http://dx.doi.org/10.1038/35001659 publisherName Nature Publishing Group title Conversion of diploidy to haploidy. mimNumber 609309 referenceNumber 72 publisherAbbreviation NPG pubmedID 10693791 source Nature 403: 723-724, 2000. authors Yan, H., Papadopoulos, N., Marra, G., Perrera, C., Jiricny, J., Boland, C. R., Lynch, H. T., Chadwick, R. B., de la Chapelle, A., Berg, K., Eshleman, J. R., Yuan, W., Markowitz, S., Laken, S. J., Lengauer, C., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://www.nature.com title A missense mutation in both hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening. mimNumber 609309 referenceNumber 73 pubmedID 10528862 source J. Med. Genet. 36: 790-793, 1999. authors Yuan, Z. Q., Wong, N., Foulkes, W. D., Alpert, L., Manganaro, F., Andreutti-Zaugg, C., Iggo, R., Anthony, K., Hsieh, E., Redston, M., Pinsky, L., Trifiro, M., Gordon, P. H., Lasko, D. pubmedImages false externalLinks cmgGene false mgiHumanDisease false hprdIDs 00389 nbkIDs NBK1211;;Lynch Syndrome refSeqAccessionIDs NG_007110.2 uniGenes Hs.597656 approvedGeneSymbols MSH2 nextGxDx true locusSpecificDBs http://www.insight-group.org/;;Hereditary Non-Polyposis Colorectal Cancer, HNPCC;;;http://www.med.mun.ca/mmrvariants/;;Mismatch Repair Genes Variant Database;;;http://databases.lovd.nl/genomed/home.php?select_db=MSH2;;Zhejiang University-Adinovo Center MSH2 Database flybaseIDs FBgn0015546 dermAtlas false umlsIDs C0879290 gtr true geneIDs 4436 swissProtIDs P43246 zfinIDs ZDB-GENE-040426-2932 ensemblIDs ENSG00000095002,ENST00000233146 geneTests true mgiIDs MGI:101816 ncbiReferenceSequences 530367624,384871700,384871701,530367622 genbankNucleotideSequences 62897278,18204305,511864202,3360507,74230052,511864203,511864201,164696094,27735351,146109029,194389127,148116998,148116999,33622357,46488017,123998192,194385857,148117000,148117001,454360,1000878,1000876,432997,110164980,123983815,1000874,110164982,15214927,1000872,28390873,110164984,1000870,34368294,110164986,1079803,19848453,1000868,1000866,62898128,194387493,194384481,1000884,1000882,13937579,1000880 proteinSequences 62897279,4557761,18204306,1171032,3360508,194385858,123998193,33622358,46488018,530367623,194389128,1000879,432998,1000877,1000875,110164981,1000873,384871702,110164983,1000871,110164985,62822548,119620619,1000869,119620618,110164987,123983816,1000867,1079805,119620620,62898129,194387494,194384482,1000885,1000883,433147,1000881 geneticsHomeReferenceIDs gene;;EPCAM;;EPCAM;;;gene;;MSH2;;MSH2

entryList

entry status live allelicVariantExists true epochCreated 946454400 geneMap geneSymbols TRPS1 sequenceID 6567 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 604386 phenotypeInheritance Autosomal dominant phenotype Trichorhinophalangeal syndrome, type I phenotypeMimNumber 190350 phenotypeMappingKey 3 mimNumber 604386 phenotypeInheritance Autosomal dominant phenotype Trichorhinophalangeal syndrome, type III phenotypeMimNumber 190351 chromosomeLocationStart 116420723 chromosomeSort 408 chromosomeSymbol 8 mimNumber 604386 geneInheritance None confidence C mappingMethod Ch, REc geneName Zinc finger transcription factor TRPS1 mouseMgiID MGI:1927616 mouseGeneSymbol Trps1 computedCytoLocation 8q23.3 cytoLocation 8q24.12 transcript uc003yny.3 chromosomeLocationEnd 116713298 chromosome 8 contributors Marla J. F. O'Neill - updated : 7/2/2014 Cassandra L. Kniffin - updated : 7/18/2011 Marla J. F. O'Neill - updated : 11/3/2009 Patricia A. Hartz - updated : 10/5/2009 Marla J. F. O'Neill - updated : 10/17/2006 George E. Tiller - updated : 3/18/2005 Natalie E. Krasikov - updated : 6/16/2004 Victor A. McKusick - updated : 2/24/2003 Victor A. McKusick - updated : 4/12/2002 Victor A. McKusick - updated : 1/17/2002 Victor A. McKusick - updated : 8/2/2001 Victor A. McKusick - updated : 1/23/2001 clinicalSynopsisExists false mimNumber 604386 allelicVariantList allelicVariant status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs121908430 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as CYS338TER (C338X) has been changed to CYS351TER (C351X). In a familial case of type I TRPS ({190350}), {13:Momeni et al. (2000)} described a 1014C-A transversion in exon 4 of the TRPS1 gene, causing a nonsense mutation, cys338 to ter. mutations TRPS1, CYS351TER number 1 clinvarAccessions RCV000005911;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs121908431 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ARG611TER (R611X) has been changed to ARG624TER (R624X). In a familial case of type I TRPS ({190350}), {13:Momeni et al. (2000)} found an 1831C-T transition in exon 4 of the TRPS1 gene, causing a nonsense mutation, arg611 to ter. mutations TRPS1, ARG624TER number 2 clinvarAccessions RCV000005912;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I text In a familial case of type I TRPS ({190350}), {13:Momeni et al. (2000)} found insertion of a single guanine between nucleotides 2406 and 2407 in exon 5 of the TRPS1 gene, causing frameshift from codon 803. mutations TRPS1, 1-BP INS, 2406G number 3 clinvarAccessions RCV000005913;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I text In a sporadic case of type I TRPS ({190350}), {13:Momeni et al. (2000)} found insertion of a T between nucleotides 2441 and 2442 in exon 5 of the TRPS1 gene, causing frameshift from codon 814. mutations TRPS1, 1-BP INS, 2441T number 4 clinvarAccessions RCV000005914;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs121908432 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ARG840TER (R840X) has been changed to ARG853TER (R853X). In a sporadic case of type I TRPS ({190350}), {13:Momeni et al. (2000)} found a 2518C-T transition in exon 5 of the TRPS1 gene, causing a nonsense mutation, arg840 to ter. mutations TRPS1, ARG853TER number 5 clinvarAccessions RCV000005915;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I text In a sporadic case of type I TRPS ({190350}), {13:Momeni et al. (2000)} found an insertion of 4 bases (GGAG) between nucleotides 3360 and 3361 in exon 7 of the TRPS1 gene, causing frameshift from codon 1121. mutations TRPS1, 4-BP INS, 3360GGAG number 6 clinvarAccessions RCV000005916;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE III dbSnps rs121908433 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as THR901PRO (T901P) has been changed to THR914PRO (T914P). In a patient with TRPS III ({190351}), who was the most severely affected patient in their study, {10:Ludecke et al. (2001)} found a thr901-to-pro missense mutation in the TRPS1 gene, which was expected to disrupt the beta-sheet structure of the GATA DNA-binding zinc finger domain and to alter the shape of the entire zinc finger. mutations TRPS1, THR914PRO number 7 clinvarAccessions RCV000005917;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs121908434 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as TYR1092TER (Y1092X) has been changed to TYR1105TER (Y1105X). {5:Hatamura et al. (2001)} described a tyr1092-to-ter (Y1092X) nonsense mutation due to a heterozygous C-to-G transversion in the TRPS1 gene in a Japanese family with type I trichorhinophalangeal syndrome ({190350}). The 40-year-old mother and all 3 of her children had thin sparse hair with recessed frontotemporo-occipital hairlines. Short stature, short arm span, facial deformity with bulbous nose and flat broad philtrum, and clinobrachydactyly of the fingers and toes were noted in all cases. Radiographs of the children showed brachymesophalangy associated with cone-shaped epiphyses in hands and feet. mutations TRPS1, TYR1105TER number 8 clinvarAccessions RCV000005918;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE III dbSnps rs121908435 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ARG908GLN (R908Q) has been changed to ARG921GLN (R921Q). {9:Kobayashi et al. (2002)} reported a Japanese family in which trichorhinophalangeal syndrome type III ({190351}) segregated with a 2723G-A substitution in exon 6 of the TRPS1 gene, resulting in an arg908-to-gln (R908Q) missense mutation. The proposita was a 59-year-old woman with short stature, thin and slow-growing hair, and brachydactyly. Her father and 2 elder sisters likewise had this disorder. She was 138 cm tall, and one of her affected sisters, aged 66 years, was 130 cm tall. Both were of normal intelligence. mutations TRPS1, ARG921GLN number 9 clinvarAccessions RCV000005919;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE III dbSnps rs121908436 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ALA919VAL (A919V) has been changed to ALA932VAL (A932V). In a case of type III trichorhinophalangeal syndrome ({190351}), {6:Hilton et al. (2002)} found a C-to-T transition at position 2756 in exon 6, causing an ala919-to-val (A919V) amino acid substitution in the GATA DNA-binding zinc finger. mutations TRPS1, ALA932VAL number 10 clinvarAccessions RCV000005920;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs28939069 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ARG952CYS (R952C) has been changed to ARG965CYS (R965C). In a father and daughter from Portugal with TRPS I ({190350}), {7:Kaiser et al. (2004)} identified heterozygosity for a 2854C-T transition in the TRPS1 gene, resulting in an arg952-to-cys (R952C) substitution. The mutation prevents the transport of the TRPS1 protein into the nucleus and thus reduces the nuclear TRPS1 concentration, consistent with haploinsufficiency. mutations TRPS1, ARG965CYS number 11 clinvarAccessions RCV000005921;;1 status live name TRICHORHINOPHALANGEAL SYNDROME, TYPE I dbSnps rs28939070 text Based on a renumbering of the TRPS1 gene sequence, the mutation originally referred to as ARG952HIS (R952H) has been changed to ARG965HIS (R965H). In a woman from Switzerland and in affected members of 4 generations of a U.S. family with TRPS I ({190350}), {7:Kaiser et al. (2004)} identified heterozygosity for a 2855G-A transition in the TRPS1 gene, resulting in an arg952-to-his (R952H) substitution. The mutation prevents the transport of the TRPS1 protein into the nucleus and thus reduces the nuclear TRPS1 concentration, consistent with haploinsufficiency. mutations TRPS1, ARG952HIS number 12 clinvarAccessions RCV000005922;;1 prefix * titles alternativeTitles TRPS1 GENE preferredTitle ZINC FINGER TRANSCRIPTION FACTOR TRPS1; TRPS1 textSectionList textSection textSectionTitle Description textSectionContent TRPS1 is a zinc finger transcriptional repressor involved in the regulation of chondrocyte and perichondrium development ({14:Napierala et al., 2008}). textSectionName description textSectionTitle Cloning textSectionContent {13:Momeni et al. (2000)} positionally cloned a gene that spanned the chromosomal breakpoint in 2 patients with trichorhinophalangeal syndrome type I (TRPS I; {190350}) and was deleted in 5 patients with TRPS I associated with an interstitial deletion. Northern blot analyses revealed transcripts of 7 and 10.5 kb. The gene, designated TRPS1, encodes a polypeptide of 1,281 amino acids. The predicted protein sequence has 2 potential nuclear localization signals (LRRRRG and RRRTRKR) and an unusual combination of different zinc finger motifs, including IKAROS-like (see {603023}) and GATA-binding (see {600576}) sequences. {7:Kaiser et al. (2004)} presented evidence that only one of the basic amino acid sequences, the RRRTRKR motif (amino acids 946-952), acts as a nuclear localization signal. textSectionName cloning textSectionTitle Gene Structure textSectionContent {13:Momeni et al. (2000)} determined that the TRPS1 gene contains 7 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent By genomic sequence analysis, {13:Momeni et al. (2000)} mapped the TRPS1 gene to chromosome 8q24. textSectionName mapping textSectionTitle Gene Function textSectionContent {8:Kaiser et al. (2003)} found that 2 distinct regions of the nuclear transcription factor TRPS1 can physically interact with the dynein light chain protein DNCL1 ({601562}). Region A covers 89 amino acids (635-723), spanning 3 potential C2H2 zinc finger structures, and region B covers the 100 most C-terminal amino acids (1182-1281) containing the IKAROS-like motif. DNCL1 colocalized with TRPS1 in dot-like structures in the cell nucleus. An electrophoretic mobility shift assay showed that the interaction of DNCL1 and TRPS1 lowered the binding of TRPS1 to the GATA consensus sequence. In addition, a GATA-regulated reporter gene assay indicated that DNCL1 could suppress the transcriptional repression activity of TRPS1. {16:Radvanyi et al. (2005)} performed a comprehensive differential gene expression screen on a panel of 54 breast tumors and more than 200 normal tissue samples and identified 15 genes specifically overexpressed in breast cancer, of which one of the most prevalent was TRPS1. The microarray findings were confirmed by in situ hybridization as well as immunoblot and immunofluorescence analysis of breast tumor cell lines. Immunohistochemistry analysis found TRPS1 protein expressed in greater than 90% of early- and late-stage breast cancer, including ductal carcinoma in situ and invasive ductal, lobular, and papillary carcinomas. After identifying 7 consensus GATA-binding sites within 3 kb of the transcriptional start site of SOX9 ({608160}), {3:Fantauzzo et al. (2012)} performed endogenous chromatin immunoprecipitation experiments in HEK293T cells and observed that TRPS1 bound up to 5 of those sites in the SOX9 promoter. Luciferase reporter promoter assays demonstrated that TRPS1 represses SOX9 transcription in a dose-dependent manner. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {13:Momeni et al. (2000)} identified 6 different nonsense mutations in the TRPS1 gene ({604386.0001}-{604386.0006}) in 10 unrelated patients with trichorhinophalangeal syndrome type I (TRPS1; {190350}). The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I. To investigate whether trichorhinophalangeal syndrome type III ({190351}) is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, {10:Ludecke et al. (2001)} performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. They found no mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III, because they had severe brachydactyly, due to short metacarpals, and severe short stature. The data indicated that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in exon 6 the TRPS1 gene. In the study of {10:Ludecke et al. (2001)}, 5 mutations were recurrent, and 4 of these were identified in patients of different ethnicities: 1 in patients of Norwegian, Turkish, and Belgian extraction, and another in patients of Belgian, Turkish, and Japanese extraction, for example. {9:Kobayashi et al. (2002)} identified a missense mutation in exon 6 of the TRPS1 gene ({604386.0009}) in type III TRPS, reinforcing the conclusion of {10:Ludecke et al. (2001)}. In cases of type III TRPS, {6:Hilton et al. (2002)} found 2 missense mutations in the GATA DNA-binding zinc finger: R908Q (now R921Q; {604386.0009}), a recurrent mutation, and A919V (now A932V; {604386.0010}), a de novo mutation. In cases of type I TRPS, {7:Kaiser et al. (2004)} identified the first 2 missense mutations that do not affect the GATA zinc finger ({604386.0011}-{604386.0012}). {11:Ludecke et al. (1995)} presented evidence that the trichorhinophalangeal syndrome type II, or Langer-Giedion syndrome ({150230}), is a contiguous gene syndrome due to loss of functional copies of both the TRPS1 and EXT1 ({608177}) genes. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent Investigations have demonstrated that most patients with nonsense mutations in the TRPS1 gene have the less severe TRPS type I phenotype ({13:Momeni et al., 2000}; {5:Hatamura et al., 2001}), while patients with missense mutations in the GATA-type zinc-finger region of the TRPS1 gene have the more severe TRPS type III phenotype ({10:Ludecke et al., 2001}; {6:Hilton et al., 2002}). {15:Piccione et al. (2009)} presented evidence supporting this hypothesis. They reported 2 unrelated patients with TRPS types I and III who had heterozygous nonsense and missense mutations, respectively, in the TRPS1 gene. The patient with type I TRPS had haploinsufficiency of TRPS1, whereas the patient with type III TRPS had an allele causing functional modification of the GATA-type motif, possibly inducing a dominant-negative effect on DNA transcription regulation and leading to a more severe phenotype. textSectionName genotypePhenotypeCorrelations textSectionTitle Cytogenetics textSectionContent {4:Fantauzzo et al. (2008)} analyzed the cytogenetic breakpoints of 3 patients with hypertrichosis universalis congenita, Ambras type (HTC1; {145701}), including patients ME-1 and SS-1, originally reported by {2:Baumeister et al. (1993)} and {1:Balducci et al. (1998)}, respectively. They identified a pericentric inversion in chromosome 8q23.1 that lies 7.3 Mb downstream of the TRPS1 gene in patient ME-1, a 6.7-Mb deletion that encompasses the TRPS1 gene in patient SS-1, and a 1.5-Mb deletion in chromosome 8q24.1 that lies 2.1 Mb upstream of the TRPS1 gene in patient BN-1. There was no overlap between the breakpoints in the 3 patients, so the authors defined the entire 11.5-Mb interval between markers RH62506 and D8S269 containing 20 genes, including the TRPS1 gene, as the candidate interval. Southern blot analysis was suggestive of deletion of TRPS1 in patient SS-1, and no RNA was available for patient BN-1. Quantitative RT-PCR demonstrated significant downregulation of TRPS1 in patient ME-1, suggesting that the inversion breakpoint 7.3 Mb downstream from the TRPS1 gene reduced expression, consistent with a position effect. {4:Fantauzzo et al. (2008)} suggested that position effect causing downregulation of TRPS1 expression is the probable cause of hypertrichosis in Ambras syndrome. textSectionName cytogenetics textSectionTitle Animal Model textSectionContent {12:Malik et al. (2002)} reported that mice heterozygous for deletion of the DNA-binding GATA domain of Trps1 (delta-GT mutation) displayed facial anomalies that overlapped with findings for TRPS, whereas mice homozygous for the delta-GT mutation additionally showed a complete absence of vibrissae. Unexpectedly, homozygous delta-GT mice died of neonatal respiratory failure resulting from abnormalities of the thoracic spine and ribs. Delta-GT heterozygotes also developed thoracic kyphoscoliosis with age and had structural deficits in cortical and trabecular bones. The findings directly implicated the GATA-type zinc finger of TRPS1 in regulation of bone and hair development and suggested that skeletal abnormalities emphasized in descriptions of TRPS are only the extreme manifestations of a generalized bone dysplasia. {14:Napierala et al. (2008)} found that mice homozygous for the Trps1 delta-GT mutation showed elongation of the growth plate due to delayed chondrocyte differentiation and abnormal mineralization of perichondrium. These abnormalities were accompanied by increased Runx2 ({600211}) and Ihh ({600726}) expression and increased Ihh signaling. Cotransfection experiments showed that wildtype Trps1 bound Runx2 and repressed Runx2-mediated activation of a reporter plasmid. Double heterozygosity for Trps1 delta-GT and a Runx2-null mutation rescued the opposite growth plate phenotypes found in single mutants. {14:Napierala et al. (2008)} concluded that TRPS1 and RUNX2 interact to regulate chondrocyte and perichondrium development. {4:Fantauzzo et al. (2008)} analyzed koala ('Koa') mice, which represent a mouse model of hypertrichosis and have a semidominant, radiation-induced chromosomal inversion near the mouse ortholog of Trps1, and found that the proximal breakpoint of the Koa inversion is located 791 kb upstream of the Trps1 gene. Quantitative RT-PCR, in situ hybridization, and immunofluorescence analysis revealed that Trps1 expression levels are reduced in Koa mutant mice at the sites of pathology for the phenotype, including muzzle and dorsal skin and cells surrounding the developing vibrissae follicles. {4:Fantauzzo et al. (2008)} determined that the Koa inversion created a new Sp1 binding site and translocated additional Sp1 binding sites within a highly conserved stretch spanning the proximal breakpoint, providing a potential mechanism for a position effect. {3:Fantauzzo et al. (2012)} studied early morphogenesis in mouse embryos homozygous for the Trps1 delta-GT mutation and observed that mutant vibrissae follicles at embryonic day (E) 16.5 were reduced in number, irregularly spaced, and smaller than wildtype vibrissae, with evidence of both an epithelial peg and dermal condensate. Development of the mutant follicles was subsequently arrested, however, and they degenerated after peg downgrowth had been initiated. Heterozygous Trps1 delta-GT embryos displayed an intermediate vibrissae phenotype, with vibrissae follicles that were slightly larger, more advanced in development, and greater in number than those observed in homozygotes, indicating a dose-dependent requirement for Trps1 in multiple hair types. Quantitative RT-PCR in whisker pad samples from homozygous Trps1 delta-GT embryos at E12.5 showed 1.80-fold upregulation of Sox9 compared to wildtype expression levels. textSectionName animalModel geneMapExists true editHistory alopez : 07/08/2014 mcolton : 7/2/2014 wwang : 7/22/2011 ckniffin : 7/18/2011 carol : 1/11/2011 wwang : 11/9/2009 terry : 11/3/2009 mgross : 10/5/2009 mgross : 10/5/2009 terry : 10/5/2009 wwang : 10/17/2006 terry : 10/17/2006 carol : 8/1/2006 alopez : 3/18/2005 carol : 6/16/2004 carol : 6/3/2004 ckniffin : 10/30/2003 carol : 10/30/2003 carol : 3/3/2003 tkritzer : 2/25/2003 terry : 2/24/2003 carol : 10/18/2002 cwells : 4/22/2002 terry : 4/12/2002 carol : 1/31/2002 mcapotos : 1/18/2002 terry : 1/17/2002 mcapotos : 8/15/2001 mcapotos : 8/14/2001 terry : 8/2/2001 joanna : 6/22/2001 carol : 1/23/2001 terry : 1/23/2001 alopez : 12/29/1999 dateCreated Wed, 29 Dec 1999 03:00:00 EST creationDate Victor A. McKusick : 12/29/1999 epochUpdated 1404802800 dateUpdated Tue, 08 Jul 2014 03:00:00 EDT referenceList reference articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1998&volume=53&issue=6&spage=466 publisherName Blackwell Publishing title A new case of Ambras syndrome associated with a paracentric inversion(8)(q12;q22). mimNumber 604386 referenceNumber 1 publisherAbbreviation Blackwell pubmedID 9712536 source Clin. Genet. 53: 466-468, 1998. authors Balducci, R., Toscano, V., Tedeschi, B., Mangiantini, A., Toscano, R., Galasso, C., Cianfarani, S., Boscherini, B. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Ambras syndrome: delineation of a unique hypertrichosis universalis congenita and association with a balanced pericentric inversion (8)(p11.2;q22). mimNumber 604386 referenceNumber 2 pubmedID 8275569 source Clin. Genet. 44: 121-128, 1993. authors Baumeister, F. A. M., Egger, J., Schildhauer, M. T., Stengel-Rutkowski, S. pubmedImages false articleUrl http://dx.plos.org/10.1371/journal.pgen.1003002 publisherName Public Library of Science title Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis. mimNumber 604386 referenceNumber 3 publisherAbbreviation PLoS pubmedID 23133399 source PLoS Genet. 8: e1003002, 2012. Note: Electronic Article. authors Fantauzzo, K. A., Kurban, M., Levy, B., Christiano, A. M. pubmedImages false publisherUrl http://www.plos.org/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18713754 publisherName HighWire Press title A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala phenotype in mice. mimNumber 604386 referenceNumber 4 publisherAbbreviation HighWire pubmedID 18713754 source Hum. Molec. Genet. 17: 3539-3551, 2008. authors Fantauzzo, K. A., Tadin-Strapps, M., You, Y., Mentzer, S. E., Baumeister, F. A. M., Cianfarani, S., Van Maldergem, L., Warburton, D., Sundberg, J. P., Christiano, A. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2001&volume=59&issue=5&spage=366 publisherName Blackwell Publishing title A nonsense mutation in TRPS1 in a Japanese family with tricho-rhino-phalangeal syndrome type I. (Letter) mimNumber 604386 referenceNumber 5 publisherAbbreviation Blackwell pubmedID 11359471 source Clin. Genet. 59: 366-367, 2001. authors Hatamura, I., Kanauchi, Y., Takahara, M., Fujiwara, M., Muragaki, Y., Ooshima, A., Ogino, T. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Analysis of novel and recurrent mutations responsible for the tricho-rhino-phalangeal syndromes. mimNumber 604386 referenceNumber 6 pubmedID 11950061 source J. Hum. Genet. 47: 103-106, 2002. authors Hilton, M. J., Sawyer, J. M., Gutierrez, L., Hogart, A., Kung, T. C., Wells, D. E. pubmedImages false articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201094 publisherName Nature Publishing Group title Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal. mimNumber 604386 referenceNumber 7 publisherAbbreviation NPG pubmedID 14560312 source Europ. J. Hum. Genet. 12: 121-126, 2004. authors Kaiser, F. J., Brega, P., Raff, M. L., Byers, P. H., Gallati, S., Kay, T. T., de Almeida, S., Horsthemke, B., Ludecke, H.-J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12761050 publisherName HighWire Press title Nuclear interaction of the dynein light chain LC8a with the TRPS1 transcription factor suppresses the transcriptional repression activity of TRPS1. mimNumber 604386 referenceNumber 8 publisherAbbreviation HighWire pubmedID 12761050 source Hum. Molec. Genet. 12: 1349-1358, 2003. authors Kaiser, F. J., Tavassoli, K., Van den Bemd, G.-J., Chang, G. T. G., Horsthemke, B., Moroy, T., Ludecke, H.-J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.10081 publisherName John Wiley & Sons, Inc. title Missense mutation of TRPS1 in a family of tricho-rhino-phalangeal syndrome type III. mimNumber 604386 referenceNumber 9 publisherAbbreviation Wiley pubmedID 11807863 source Am. J. Med. Genet. 107: 26-29, 2002. authors Kobayashi, H., Hino, M., Shimodahira, M., Iwakura, T., Ishihara, T., Ikekubo, K., Ogawa, Y., Nakao, K., Kurahachi, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62473-2 publisherName Elsevier Science title Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. mimNumber 604386 referenceNumber 10 publisherAbbreviation ES pubmedID 11112658 source Am. J. Hum. Genet. 68: 81-91, 2001. authors Ludecke, H.-J., Schaper, J., Meinecke, P., Momeni, P., Gross, S., von Holtum, D., Hirche, H., Abramowicz, M. J., Albrecht, B., Apacik, C., Christen, H.-J., Claussen, U., {and 28 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7711731 publisherName HighWire Press title Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. mimNumber 604386 referenceNumber 11 publisherAbbreviation HighWire pubmedID 7711731 source Hum. Molec. Genet. 4: 31-36, 1995. authors Ludecke, H.-J., Wagner, M. J., Nardmann, J., La Pillo, B., Parrish, J. E., Willems, P. J., Haan, E. A., Frydman, M., Hamers, G. J. H., Wells, D. E., Horsthemke, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=12446778 publisherName HighWire Press title Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes. mimNumber 604386 referenceNumber 12 publisherAbbreviation HighWire pubmedID 12446778 source Molec. Cell. Biol. 22: 8592-8600, 2002. authors Malik, T. H., von Stechow, D., Bronson, R. T., Shivdasani, R. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/71717 publisherName Nature Publishing Group title Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. mimNumber 604386 referenceNumber 13 publisherAbbreviation NPG pubmedID 10615131 source Nature Genet. 24: 71-74, 2000. authors Momeni, P., Glockner, G., Schmidt, O., von Holtum, D., Albrecht, B., Gillessen-Kaesbach, G., Hennekam, R., Meinecke, P., Zabel, B., Rosenthal, A., Horsthemke, B., Ludecke, H.-J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18424451 publisherName HighWire Press title Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. mimNumber 604386 referenceNumber 14 publisherAbbreviation HighWire pubmedID 18424451 source Hum. Molec. Genet. 17: 2244-2254, 2008. authors Napierala, D., Sam, K., Morello, R., Zheng, Q., Munivez, E., Shivdasani, R. A., Lee, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.32952 publisherName John Wiley & Sons, Inc. title Identification of two new mutations in TRPS 1 gene leading to the tricho-rhino-phalangeal syndrome type I and III. (Letter) mimNumber 604386 referenceNumber 15 publisherAbbreviation Wiley pubmedID 19610100 source Am. J. Med. Genet. 149A: 1837-1841, 2009. authors Piccione, M., Niceta, M., Antona, V., Di Fiore, A., Cariola, F., Gentile, M., Corsello, G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16043716 publisherName HighWire Press title The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer. mimNumber 604386 referenceNumber 16 publisherAbbreviation HighWire pubmedID 16043716 source Proc. Nat. Acad. Sci. 102: 11005-11010, 2005. authors Radvanyi, L., Singh-Sandhu, D., Gallichan, S., Lovitt, C., Pedyczak, A., Mallo, G., Gish, K., Kwok, K., Hanna, W., Zubovits, J., Armes, J., Venter, D., Hakimi, J., Shortreed, J., Donovan, M., Parrington, M., Dunn, P., Oomen, R., Tartaglia, J., Berinstein, N. L. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:1927616 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 530389292,530389288,530389290,530389286,574957114 refSeqAccessionIDs NG_012383.2 dermAtlas false hprdIDs 05091 swissProtIDs Q9UHF7 zfinIDs ZDB-GENE-030131-8404 uniGenes Hs.657018 gtr true cmgGene false ensemblIDs ENSG00000104447,ENST00000395715 umlsIDs C1421175 genbankNucleotideSequences 478414084,478414085,478414086,478414080,148154385,478414081,148154386,478414082,148154387,478414083,71518148,7021932,529605592,10432662,527462651,527462652,527462653,511808847,115527468,6684533,164689344,529161171,10432707,146017066,529161173,527462673,478414068,529161080,529161144,478414071,80918119,478414066,527466566,478414067,478414076,527462664,478414077,194384367,478414078,478414079,10644121,529161078,478414073,42794098,478414075 geneTests true approvedGeneSymbols TRPS1 geneIDs 7227 proteinSequences 578816132,544710995,7021933,194384368,578816134,119612358,544711007,115527469,530389293,6684534,90652851,10644122,20140909 geneticsHomeReferenceIDs gene;;TRPS1;;TRPS1

entryList

entry status live allelicVariantExists true epochCreated 927183600 geneMap geneSymbols GNE, GLCNE, IBM2, DMRV, NM sequenceID 6860 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 603824 phenotypeInheritance Autosomal recessive phenotype Inclusion body myopathy, autosomal recessive phenotypeMimNumber 600737 phenotypeMappingKey 3 mimNumber 603824 phenotypeInheritance Autosomal recessive phenotype Nonaka myopathy phenotypeMimNumber 605820 phenotypeMappingKey 3 mimNumber 603824 phenotypeInheritance Autosomal dominant phenotype Sialuria phenotypeMimNumber 269921 chromosomeLocationStart 36214437 chromosomeSort 163 chromosomeSymbol 9 mimNumber 603824 geneInheritance None confidence C mappingMethod TM, R, Fd geneName UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase mouseMgiID MGI:1354951 mouseGeneSymbol Gne computedCytoLocation 9p13.3 cytoLocation 9p13.3 transcript uc010mli.3 chromosomeLocationEnd 36277052 chromosome 9 contributors Cassandra L. Kniffin - updated : 9/2/2009 Cassandra L. Kniffin - updated : 8/10/2009 Marla J. F. O'Neill - updated : 8/1/2007 Marla J. F. O'Neill - updated : 4/6/2006 Cassandra L. Kniffin - reorganized : 2/25/2005 Cassandra L. Kniffin - updated : 2/21/2005 Cassandra L. Kniffin - updated : 8/19/2003 Cassandra L. Kniffin - updated : 1/17/2003 Cassandra L. Kniffin - updated : 12/6/2002 Cassandra L. Kniffin - updated : 10/7/2002 Victor A. McKusick - updated : 5/31/2002 Victor A. McKusick - updated : 3/19/2002 Victor A. McKusick - updated : 6/20/2001 Victor A. McKusick - updated : 1/13/2000 Victor A. McKusick - updated : 1/13/2000 Victor A. McKusick - updated : 6/2/1999 clinicalSynopsisExists false mimNumber 603824 allelicVariantList allelicVariant status live name SIALURIA dbSnps rs121908621 text In a patient with sialuria ({269921}) who was originally described by {25:Wilcken et al. (1987)}, {19:Seppala et al. (1999)} identified a C-to-T transition in the third base of codon 266 of the GNE gene, resulting in an arg266-to-trp substitution. mutations GNE, ARG266TRP number 1 clinvarAccessions RCV000006392;;2 status live name SIALURIA dbSnps rs121908622 text In a patient with sialuria ({269921}) who was originally described by {24:Weiss et al. (1989)}, {19:Seppala et al. (1999)} identified a G-to-A transition in the second base of codon 266 of the GNE gene, resulting in an arg266-to-gln (R266Q) substitution. {13:Leroy et al. (2001)} described heterozygosity for the R266Q mutation in the GNE gene in a child with sialuria. His mother was found to carry the same heterozygous mutation, confirming dominant inheritance of the disorder. In contrast to all 4 of her sisters, who had graduated from various college-level training programs, the mother had completed only grade school and held domestic employment briefly before marriage. She was of normal stature without dysmorphic features. The urinary level of free NeuAc was elevated. The father, who was unrelated to the mother, had normal urinary findings. At 2 months of age the child had frequent opisthotonic posturing and persistent hypotonia. Anemia required transfusion of packed red blood cells. Excessive rhinorrhea and recurrent respiratory infections were present throughout infancy. Impaired hip and knee extensions were noted at age 15 months. The boy remained hypotonic but alert and physically active. Skeletal x-rays at age 10.5 months showed a skeletal age between 3 and 6 months and mildly widened long bone diaphyses and widened metaphyses of some bones of the limbs. mutations GNE, ARG266GLN number 2 clinvarAccessions RCV000006393;;2 status live name SIALURIA dbSnps rs121908623 text In a patient with sialuria ({269921}) who was originally described by {12:Krasnewich et al. (1993)}, {19:Seppala et al. (1999)} identified a G-to-T transversion in the second base of codon 263 of the GNE gene, resulting in an arg263-to-leu substitution. mutations GNE, ARG263LEU number 3 clinvarAccessions RCV000006394;;2 status moved number 4 name MOVED TO {603824.0002} movedTo 603824.0002 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs28937594 text In 47 Middle Eastern Jewish families, {4:Eisenberg et al. (2001)} found that affected individuals with quadriceps-sparing inclusion body myopathy-2 (IBM2; {600737}) had a 2186T-C transition in exon 12 of the GNE gene, resulting in a met712-to-thr (M712T) amino acid change in the kinase domain of the protein. In 2 second cousins from an Italian family with IBM2, {3:Broccolini et al. (2002)} identified compound heterozygosity for mutations in the GNE gene: M712T and a novel mutation (M171V; {603824.0016}). The authors noted that it was the first report of the M712T mutation in patients of non-Middle Eastern descent. {2:Argov et al. (2003)} identified homozygosity for the M712T mutation in 129 Middle Eastern patients with IBM2 from 55 families. Eleven patients had atypical features: 5 had involvement of the quadriceps muscle, 2 patients did not have distal weakness, 3 patients had facial weakness, and 1 patient had perivascular inflammation. There were 5 unaffected individuals with the homozygous mutation from 5 different IBM2 families, including 2 who were 50 and 68 years old. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. {2:Argov et al. (2003)} offered a detailed historical perspective of the different cultures, and concluded that this founder mutation is approximately 1,300 years old and is not limited to those of Jewish descent. In a Japanese patient with Nonaka myopathy ({605820}), {22:Tomimitsu et al. (2004)} identified compound heterozygosity for the M712T mutation and the A631V mutation ({603824.0015}). The findings indicated that Nonaka myopathy and IBM2 are allelic, if not identical, disorders. mutations GNE, MET712THR number 5 alternativeNames NONAKA MYOPATHY, INCLUDED clinvarAccessions RCV000006396;;2;;;RCV000006395;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908625 text In a Georgia (USA) family, {4:Eisenberg et al. (2001)} found that autosomal recessive inclusion body myopathy ({600737}) was caused by compound heterozygosity for a gly576-to-glu (G576E) mutation and an ala631-to-thr (A631T; {603824.0007}) mutation in the GNE gene. mutations GNE, GLY576GLU number 6 clinvarAccessions RCV000006397;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908626 text See {603824.0006} and {4:Eisenberg et al. (2001)}. mutations GNE, ALA631THR number 7 clinvarAccessions RCV000006398;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908627 text In affected members of an Asiatic Indian family with autosomal recessive inclusion body myopathy ({600737}), {4:Eisenberg et al. (2001)} found compound heterozygosity for 2 missense mutations, val696 to met (V696M) and cys303 to ter (C303X; {603824.0009}), in the GNE gene. mutations GNE, VAL696MET number 8 clinvarAccessions RCV000006399;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908628 text See {603824.0008} and {4:Eisenberg et al. (2001)}. mutations GNE, CYS303TER number 9 clinvarAccessions RCV000006400;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908629 text In a family from the Bahamas with autosomal recessive inclusion body myopathy ({600737}), {4:Eisenberg et al. (2001)} found compound heterozygosity for 2 missense mutations in the GNE gene: arg246 to gln (R246Q) and asp225 to asn (D225N; {603824.0011}). Both mutations were in exon 4 and the amino acid changes involved the epimerase domain of the protein. mutations GNE, ARG246GLN number 10 clinvarAccessions RCV000006401;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908630 text See {603824.0010} and {4:Eisenberg et al. (2001)}. mutations GNE, ASP225ASN number 11 clinvarAccessions RCV000006402;;1 status live name NONAKA MYOPATHY dbSnps rs121908631 text In 2 sibs with distal myopathy with rimmed vacuoles, or Nonaka myopathy ({605820}), {9:Kayashima et al. (2002)} found compound heterozygosity in the GNE gene for a C-to-T transition in exon 8, resulting in an ala460-to-val (A460V) substitution, and a G-to-C transition in exon 10, resulting in a V572L ({603824.0013}) substitution. mutations GNE, ALA460VAL number 12 clinvarAccessions RCV000006403;;1 status live name NONAKA MYOPATHY dbSnps rs121908632 text See {603824.0012} and {9:Kayashima et al. (2002)}. In 7 of 9 unrelated Japanese patients with Nonaka myopathy ({605820}), {21:Tomimitsu et al. (2002)} identified a homozygous 1765G-C transition in exon 10 of the GNE gene, resulting in a val572-to-leu (V572L) substitution. An eighth patient was a compound heterozygote for V572L and C303V ({603824.0014}). {1:Arai et al. (2002)} identified the V572L mutation in patients with Nonaka myopathy from 6 consanguineous Japanese families. Haplotype analysis indicated a strong founder effect in these pedigrees. Mean age of onset was 23 years, and most cases became nonambulant within 10 years of disease onset. {22:Tomimitsu et al. (2004)} identified the V572L mutation in 15 of 22 patients with Nonaka myopathy: 9 were homozygous and 6 were compound heterozygous for V572L and another mutation in the GNE gene. {11:Kim et al. (2006)} identified the V572L mutation in 7 of 8 unrelated Korean patients with Nonaka myopathy: 4 were homozygous and 3 were compound heterozygous for V572L and another mutation in the GNE gene. mutations GNE, VAL572LEU number 13 clinvarAccessions RCV000006404;;2 status live name NONAKA MYOPATHY dbSnps rs121908633 text In a patient with Nonaka myopathy ({605820}), {21:Tomimitsu et al. (2002)} identified 2 nucleotide substitutions in the GNE gene, 958-959TG-GT, resulting in a cys303-to-val (C303V) change. The patient was a compound heterozygote for this mutation and V572L ({603824.0013}). mutations GNE, CYS303VAL number 14 clinvarAccessions RCV000006405;;1 status live name NONAKA MYOPATHY dbSnps rs62541771 text In 1 of 9 unrelated Japanese patients with Nonaka myopathy ({605820}), {21:Tomimitsu et al. (2002)} identified a homozygous 1943C-T transition in exon 11 of the GNE gene, resulting in an ala631-to-val (A631V) substitution. Of the 9 patients, this patient had the latest age of onset, the slowest progression of disease, and was still able to stand 30 years after onset. mutations GNE, ALA631VAL number 15 clinvarAccessions RCV000006406;;1 status live name INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE dbSnps rs121908634 text In 2 second cousins from an Italian family with IBM2 ({600737}), {3:Broccolini et al. (2002)} identified compound heterozygosity for mutations in the GNE gene: a 562A-to-G transition in exon 3, resulting in a met171-to-val substitution (M171V) and M712T ({603824.0005}). mutations GNE, MET171VAL number 16 clinvarAccessions RCV000006407;;1 prefix * titles alternativeTitles GLCNE preferredTitle UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; GNE textSectionList textSection textSectionTitle Description textSectionContent Sialic acid modification of glycoproteins and glycolipids expressed at the cell surface is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. GNE is the rate-limiting enzyme in the sialic acid biosynthetic pathway ({10:Keppler et al., 1999}). {6:Hinderlich et al. (1997)} reported that biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids, in rat liver is initiated and regulated by a bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; {EC 5.1.3.14})/N-acetylmannosamine kinase (ManNAc kinase; {EC 2.7.1.60}). textSectionName description textSectionTitle Cloning textSectionContent {20:Stasche et al. (1997)} isolated rat cDNAs encoding the UDP-N-acetylglucosamine 2-epimerase. Secreting organs, such as liver, salivary glands, and intestinal mucosa, showed high UDP-GlcNAc 2-epimerase/ManNAc kinase activity. {10:Keppler et al. (1999)} determined that UDP-GlcNAc 2-epimerase activity is rate-limiting for the biosynthesis of sialic acid and is required for sialylation in hematopoietic cells. The activity of the enzyme can be controlled at the transcriptional level and can affect the sialylation and function of specific cell surface molecules expressed on B cells and myeloid cells. In a Genbank submission ({GENBANK AJ238764}), these authors reported the sequence of a human UDP-GlcNAc 2-epimerase cDNA. {22:Tomimitsu et al. (2004)} identified 2 isoforms of GNE: a longer form, comprising 556 bp, and a shorter form, with exon 4 missing and comprising 403 bp. The shorter isoform was predominantly expressed in skeletal muscle, whereas the longer isoform was predominantly expressed in all other tissues. The shorter isoform was expressed in skeletal muscle of both controls and patients with distal myopathy with rimmed vacuoles ({605820}), with no difference between the 2 groups. textSectionName cloning textSectionTitle Mapping textSectionContent By analysis of a mouse-human cell hybrid panel, {7:Huizing and Anikster (2000)} assigned the gene that is mutant in sialuria to chromosome 9p12-p11. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Sialuria Sialuria ({269921}) is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free NeuAc. Overproduction of NeuAc was believed to result from loss of feedback inhibition of UDP-GlcNAc 2-epimerase by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). To elucidate the molecular mechanism for defective allosteric regulation of UDP-GlcNAc 2-epimerase in this disease, {19:Seppala et al. (1999)} cloned and sequenced the human cDNA encoding the epimerase and determined the mutations in 3 sialuria patients. Three heterozygous mutations, arg266 to trp ({603824.0001}), arg266 to gln ({603824.0002}), and arg263 to leu ({603824.0003}), indicated that the allosteric site of the epimerase resides in the region of codons 263 to 266. The absence of any symptoms in the parents of the affected children indicated that the base changes represented new mutations. Parental DNA was not available for direct analysis. The heterozygous nature of the mutant allele in all 3 patients demonstrated dominant inheritance of sialuria, i.e., heterozygosity for a mutation in the allosteric site is sufficient to cause the disorder. In this case, the mutant epimerase activity continues to produce free sialic acid and CMP-Neu5Ac, which inhibits the normal but not the mutant epimerase. With no brake on the rate-limiting step in sialic acid production, intracellular free sialic acid levels increase indefinitely, leading to the clinical and laboratory findings of sialuria. Dominant inheritance has also been reported in the syndrome of hyperinsulinism and hyperammonemia, in which GTP fails to feedback-inhibit glutamate dehydrogenase ({138130}) because of mutations affecting the enzyme's allosteric site (see {138130.0003}). Autosomal Recessive Inclusion Body Myopathy 2 and Nonaka Myopathy Hereditary inclusion body myopathy (IBM) constitutes a unique group of neuromuscular disorders characterized by adult-onset slowly progressive distal and proximal weakness, and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. Autosomal dominant (IBM3; {605637}) and autosomal recessive (IBM2; {600737}) forms have been described. The autosomal recessive form, first characterized in Jews of Persian descent, is a myopathy that affects mainly leg muscles, but with an unusual distribution that spares the quadriceps, so-called quadriceps-sparing myopathy (QSM). This disorder was subsequently found in other Middle Eastern families, the gene was mapped to 9p13-p12, and in 104 affected persons from 47 Middle Eastern families the same mutation in homozygous state was found in the GNE gene ({4:Eisenberg et al., 2001}). Affected individuals in families of other ethnic origins were found to be compound heterozygotes for other distinct mutations in the GNE gene. {4:Eisenberg et al. (2001)} urged the study of GNE in Nonaka distal myopathy ({605820}) with rimmed vacuoles, described in Japanese patients ({17:Nonaka et al., 1981}) and found to map to the same region of chromosome 9 ({8:Ikeuchi et al., 1997}) as autosomal recessive inclusion body myopathy. Furthermore, {4:Eisenberg et al. (2001)} suggested investigating GNE involvement in sporadic inclusion body myositis, which occurs worldwide and is the most common myopathy in individuals aged 50 and older. {9:Kayashima et al. (2002)} performed sequence and haplotype analysis of the GNE gene in 2 sibs with Nonaka myopathy and demonstrated compound heterozygosity for 2 missense mutations ({603284.0012}, {603284.0013}) in both. Their parents and a normal elder brother were all carriers for 1 or the other of the mutations. This was the third disorder related to mutations in the GNE gene. Mutations associated with sialuria are located in the epimerase domain, and those associated with IBM2 are in the epimerase or the kinase domain or both, whereas the mutations observed by {9:Kayashima et al. (2002)} in Nonaka myopathy are located in the sugar kinase domain of the gene. Among 33 Japanese patients and 1 patient of German and Irish ancestry with Nonaka myopathy, {16:Nishino et al. (2002)} identified homozygous or compound heterozygous mutations in the GNE gene in 27 unrelated patients. An unaffected father of 1 patient had a homozygous mutation that presumably caused disease in other patients. The V572L mutation ({603824.0013}) accounted for 61% of the abnormal alleles in the study, indicating a high frequency of carriers of this mutation in Japan. The authors noted that the patient of German and Irish ancestry had a compound mutation, although not the V572L mutation, indicating that the disorder is not restricted to Japan. In an American patient with IBM2, {23:Vasconcelos et al. (2002)} identified compound heterozygosity for mutations in the GNE gene, expanding the genetic heterogeneity of the disorder. No mutation in the GNE gene was detected in 11 sporadic IBM patients. {22:Tomimitsu et al. (2004)} identified mutations in the GNE gene in 20 of 22 patients diagnosed with Nonaka myopathy. Fifteen patients had the V572L mutation, either in the homozygous or compound heterozygous form. The authors also identified 7 novel GNE mutations. One patient carried the met712-to-thr mutation (M712T; {603824.0005}), confirming that inclusion body myopathy and Nonaka myopathy are allelic disorders. {11:Kim et al. (2006)} performed clinical and genetic analysis of 9 unrelated Korean patients suspected of having Nonaka myopathy and found that 8 of the 9 were homozygous or compound heterozygous for mutations in the GNE gene. The allelic frequencies of the V572L and C13S mutations were 68.8% and 12.5%, respectively. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {18:Schwarzkopf et al. (2002)} reported that inactivation of GNE (which is bifunctional and the key enzyme of sialic acid biosynthesis) by gene targeting in mice caused early embryonic lethality, thereby emphasizing the fundamental role of the enzyme and sialylation during development. The need for the enzyme for a defined sialylation process is exemplified by the polysialylation of the neural cell adhesion molecule in embryonic stem cells. {5:Galeano et al. (2007)} created knockin mice with the M712T Gne mutation and found that homozygous mutants did not survive beyond postnatal day 3. On postnatal day 2, there was significantly decreased Gne activity in muscle but no myopathic features; rather, the homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy, with segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of podocalyxin (see {602632}). With administration of ManNAc, 43% of homozygous mutants survived beyond postnatal day 3, exhibiting improved renal histology, increased sialylation of podocalyxin, and increased Gne expression and activity. {5:Galeano et al. (2007)} concluded that M712T Gne-knockin mice provide a novel animal model of hyposialylation-related podocytopathy and segmental splitting of the glomerular basement membrane, demonstrating the significance of sialic acid synthesis in kidney development and function. {15:Malicdan et al. (2007)} generated Gne-deficient mice expressing the human D176V-GNE mutation as a mouse model of distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy (DMRV-HIBM). Complete knockout of the Gne gene was embryonic lethal. Mice with the D176V mutation showed marked hyposialylation in serum, muscle, and other organs. Reduction in motor performance in these mice could only be seen from 30 weeks of age. By 32 weeks, myofibers developed beta-amyloid deposition, which preceded rimmed vacuole formation at 42 weeks. The findings also suggested that hyposialylation plays an important role in the pathomechanism of DMRV-HIBM. {14:Malicdan et al. (2009)} found that D176V-mutant mice treated orally with sialic acid showed increased survival, increased motor performance, and decreased number of rimmed vacuoles in skeletal muscle compared to untreated mice with the disorder. Prophylactic treatment prevented development of the myopathic phenotype. The findings indicated that hyposialylation is a key factor in the pathomechanism of DMRV-HIBM. textSectionName animalModel geneMapExists true editHistory carol : 01/02/2014 carol : 1/2/2014 carol : 1/2/2014 carol : 3/21/2013 ckniffin : 6/29/2011 wwang : 9/9/2009 ckniffin : 9/2/2009 wwang : 8/10/2009 wwang : 4/1/2009 wwang : 8/13/2007 terry : 8/1/2007 wwang : 4/10/2006 terry : 4/6/2006 ckniffin : 6/30/2005 tkritzer : 2/25/2005 tkritzer : 2/25/2005 ckniffin : 2/21/2005 tkritzer : 1/5/2004 cwells : 8/19/2003 ckniffin : 8/18/2003 carol : 1/24/2003 ckniffin : 1/21/2003 ckniffin : 1/17/2003 ckniffin : 1/17/2003 carol : 12/6/2002 ckniffin : 12/6/2002 carol : 11/1/2002 tkritzer : 10/29/2002 ckniffin : 10/7/2002 cwells : 6/6/2002 cwells : 6/5/2002 terry : 5/31/2002 cwells : 4/3/2002 cwells : 3/21/2002 terry : 3/19/2002 alopez : 8/27/2001 alopez : 8/27/2001 terry : 8/23/2001 mcapotos : 6/26/2001 mcapotos : 6/21/2001 terry : 6/20/2001 carol : 1/13/2000 terry : 1/13/2000 kayiaros : 7/13/1999 mgross : 6/9/1999 mgross : 6/8/1999 mgross : 6/2/1999 alopez : 5/21/1999 alopez : 5/21/1999 dateCreated Thu, 20 May 1999 03:00:00 EDT creationDate Rebekah S. Rasooly : 5/20/1999 epochUpdated 1388649600 dateUpdated Thu, 02 Jan 2014 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1002/ana.10341 publisherName John Wiley & Sons, Inc. title A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees. mimNumber 603824 referenceNumber 1 publisherAbbreviation Wiley pubmedID 12325084 source Ann. Neurol. 52: 516-519, 2002. authors Arai, A., Tanaka, K., Ikeuchi, T., Igarashi, S., Kobayashi, H., Asaka, T., Date, H., Saito, M., Tanaka, H., Kawasaki, S., Uyama, E., Mizusawa, H., Fukuhara, N., Tsuji, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12743242 publisherName HighWire Press title Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. mimNumber 603824 referenceNumber 2 publisherAbbreviation HighWire pubmedID 12743242 source Neurology 60: 1519-1523, 2003. authors Argov, Z., Eisenberg, I., Grabov-Nardini, G., Sadeh, M., Wirguin, I., Soffer, D., Mitrani-Rosenbaum, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12473780 publisherName HighWire Press title An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene. mimNumber 603824 referenceNumber 3 publisherAbbreviation HighWire pubmedID 12473780 source Neurology 59: 1808-1809, 2002. authors Broccolini, A., Pescatori, M., D'Amico, A., Sabino, A., Silvestri, G., Ricci, E., Servidei, S., Tonali, P. A., Mirabella, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng718 publisherName Nature Publishing Group title The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. mimNumber 603824 referenceNumber 4 publisherAbbreviation NPG pubmedID 11528398 source Nature Genet. 29: 83-87, 2001. authors Eisenberg, I., Avidan, N., Potikha, T., Hochner, H., Chen, M., Olender, T., Barash, M., Shemesh, M., Sadeh, M., Grabov-Nardini, G., Shmilevich, I., Friedmann, A., Karpati, G., Bradley, W. G., Baumbach, L., Lancet, D., Ben Asher, E., Beckmann, J. S., Argov, Z., Mitrani-Rosenbaum, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1172/JCI30954 publisherName Journal of Clinical Investigation title Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. mimNumber 603824 referenceNumber 5 publisherAbbreviation JCI pubmedID 17549255 source J. Clin. Invest. 117: 1585-1594, 2007. authors Galeano, B., Klootwijk, R., Manoli, I., Sun, M., Ciccone, C., Darvish, D., Starost, M. F., Zerfas, P. M., Hoffmann, V. J., Hoogstraten-Miller, S., Krasnewich, D. M., Gahl, W. A., Huizing, M. pubmedImages true publisherUrl http://www.jci.org articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9305887 publisherName HighWire Press title A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver: purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. mimNumber 603824 referenceNumber 6 publisherAbbreviation HighWire pubmedID 9305887 source J. Biol. Chem. 272: 24313-24318, 1997. authors Hinderlich, S., Stasche, R., Zeitler, R., Reutter, W. pubmedImages false publisherUrl http://highwire.stanford.edu source Bethesda, Md. 1/10/2000. mimNumber 603824 authors Huizing, M., Anikster, Y. title Personal Communication. referenceNumber 7 title Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9. mimNumber 603824 referenceNumber 8 pubmedID 9124799 source Ann. Neurol. 41: 432-437, 1997. authors Ikeuchi, T., Asaka, T., Saito, M., Tanaka, H., Higuchi, S., Tanaka, K., Saida, K., Uyama, E., Mizusawa, H., Fukuhara, N., Nonaka, I., Takamori, M., Tsuji, S. pubmedImages false title Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). mimNumber 603824 referenceNumber 9 pubmedID 11916006 source J. Hum. Genet. 47: 77-79, 2002. authors Kayashima, T., Matsuo, H., Satoh, A., Ohta, T., Yoshiura, K., Matsumoto, N., Nakane, Y., Niikawa, N., Kishino, T. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=10334995 publisherName HighWire Press title UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. mimNumber 603824 referenceNumber 10 publisherAbbreviation HighWire pubmedID 10334995 source Science 284: 1372-1376, 1999. authors Keppler, O. T., Hinderlich, S., Langner, J., Schwartz-Albiez, R., Reutter, W., Pawlita, M. pubmedImages false publisherUrl http://highwire.stanford.edu title Mutation analysis of the GNE gene in Korean patients with distal myopathy with rimmed vacuoles. mimNumber 603824 referenceNumber 11 pubmedID 16372135 source J. Hum. Genet. 51: 137-140, 2006. Note: Erratum: J. Hum. Genet. 51: 840 only, 2006. authors Kim, B. J., Ki, C.-S., Kim, J.-W., Sung, D. H., Choi, Y.-C., Kim, S. H. pubmedImages false title Clinical and biochemical studies in an American child with sialuria. mimNumber 603824 referenceNumber 12 pubmedID 8439453 source Biochem. Med. Metab. Biol. 49: 90-96, 1993. authors Krasnewich, D. M., Tietze, F., Krause, W., Pretzlaff, R., Wenger, D. A., Diwadkar, V., Gahl, W. A. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61052-0 publisherName Elsevier Science title Dominant inheritance of sialuria, an inborn error of feedback inhibition. mimNumber 603824 referenceNumber 13 publisherAbbreviation ES pubmedID 11326336 source Am. J. Hum. Genet. 68: 1419-1427, 2001. authors Leroy, J. G., Seppala, R., Huizing, M., Dacremont, G., De Simpel, H., Van Coster, R. N., Orvisky, E., Krasnewich, D. M., Gahl, W. A. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nm.1956 publisherName Nature Publishing Group title Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. mimNumber 603824 referenceNumber 14 publisherAbbreviation NPG pubmedID 19448634 source Nature Med. 15: 690-695, 2009. authors Malicdan, M. C. V., Noguchi, S., Hayashi, Y. K., Nonaka, I., Nishino, I. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17704511 publisherName HighWire Press title A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. mimNumber 603824 referenceNumber 15 publisherAbbreviation HighWire pubmedID 17704511 source Hum. Molec. Genet. 16: 2669-2682, 2007. authors Malicdan, M. C. V., Noguchi, S., Nonaka, I., Hayashi, Y. K., Nishino, I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12473753 publisherName HighWire Press title Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. mimNumber 603824 referenceNumber 16 publisherAbbreviation HighWire pubmedID 12473753 source Neurology 59: 1689-1693, 2002. authors Nishino, I., Noguchi, S., Murayama, K., Driss, A., Sugie, K., Oya, Y., Nagata, T., Chida, K., Takahashi, T., Takusa, Y., Ohi, T., Nishiyama, J., Sunohara, N., Ciafaloni, E., Kawai, M., Aoki, M., Nonaka, I. pubmedImages false publisherUrl http://highwire.stanford.edu title Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. mimNumber 603824 referenceNumber 17 pubmedID 7252518 source J. Neurol. Sci. 51: 141-155, 1981. authors Nonaka, I., Sunohara, N., Ishiura, S., Satoyoshi, E. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11929971 publisherName HighWire Press title Sialylation is essential for early development in mice. mimNumber 603824 referenceNumber 18 publisherAbbreviation HighWire pubmedID 11929971 source Proc. Nat. Acad. Sci. 99: 5267-5270, 2002. authors Schwarzkopf, M., Knobeloch, K.-P., Rohde, E., Hinderlich, S., Wiechens, N., Lucka, L., Horak, I., Reutter, W., Horstkorte, R. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63658-1 publisherName Elsevier Science title Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. mimNumber 603824 referenceNumber 19 publisherAbbreviation ES pubmedID 10330343 source Am. J. Hum. Genet. 64: 1563-1569, 1999. authors Seppala, R., Lehto, V.-P., Gahl, W. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9305888 publisherName HighWire Press title A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver: molecular cloning and functional expression of UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase. mimNumber 603824 referenceNumber 20 publisherAbbreviation HighWire pubmedID 9305888 source J. Biol. Chem. 272: 24319-24324, 1997. authors Stasche, R., Hinderlich, S., Weise, C., Effertz, K., Lucka, L., Moormann, P., Reutter, W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12177386 publisherName HighWire Press title Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. mimNumber 603824 referenceNumber 21 publisherAbbreviation HighWire pubmedID 12177386 source Neurology 59: 451-454, 2002. authors Tomimitsu, H., Ishikawa, K., Shimizu, J., Ohkoshi, N., Kanazawa, I., Mizusawa, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15136692 publisherName HighWire Press title Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. mimNumber 603824 referenceNumber 22 publisherAbbreviation HighWire pubmedID 15136692 source Neurology 62: 1607-1610, 2004. authors Tomimitsu, H., Shimizu, J., Ishikawa, K., Ohkoshi, N., Kanazawa, I., Mizusawa, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12473769 publisherName HighWire Press title GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. mimNumber 603824 referenceNumber 23 publisherAbbreviation HighWire pubmedID 12473769 source Neurology 59: 1776-1779, 2002. authors Vasconcelos, O. M., Raju, R., Dalakas, M. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2808337 publisherName HighWire Press title Identification of the metabolic defect in sialuria. mimNumber 603824 referenceNumber 24 publisherAbbreviation HighWire pubmedID 2808337 source J. Biol. Chem. 264: 17635-17636, 1989. authors Weiss, P., Tietze, F., Gahl, W. A., Seppala, R., Ashwell, G. pubmedImages false publisherUrl http://highwire.stanford.edu title Sialuria: a second case. mimNumber 603824 referenceNumber 25 pubmedID 2443758 source J. Inherit. Metab. Dis. 10: 97-102, 1987. authors Wilcken, B., Don, N., Greenaway, R., Hammond, J., Sosula, L. pubmedImages false externalLinks cmgGene false mgiHumanDisease false hprdIDs 04825 nbkIDs NBK1164;;Sialuria;;;NBK1262;;GNE-Related Myopathy refSeqAccessionIDs NG_008246.1 uniGenes Hs.5920 approvedGeneSymbols GNE nextGxDx true locusSpecificDBs http://www.LOVD.nl/GNE;;GNE database at LOVD dermAtlas false umlsIDs C1428183 gtr true geneIDs 10020 swissProtIDs Q9Y223 zfinIDs ZDB-GENE-040426-1848 ensemblIDs ENSG00000159921,ENST00000396594 geneTests true mgiIDs MGI:1354951 ncbiReferenceSequences 298566314,530389633,298566311,298566310,298566309,298566324 genbankNucleotideSequences 221040813,146085811,150368574,20399359,4775361,19621984,11121380,19724347,156186264,45360236,5031509,45360232,45360234,19721651,4887657,52051709,146022877,11087557,221041473,148141732,74230045,164690338,24994190,148141730,150368576,115528468,148141731,511807935,511807934,11139286 proteinSequences 4887658,298566315,221040814,298566312,189069100,150368575,45476991,4775362,221041474,4885285,156186265,119578711,150368577,119578712,119578713,45360237,5031510,190014632,45360233,11139287,298566325,45360235,111309277,530389634 geneticsHomeReferenceIDs gene;;GNE;;GNE

entryList

entry status live allelicVariantExists true epochCreated 755424000 geneMap geneSymbols MLH1, COCA2, HNPCC2 sequenceID 2586 phenotypeMapList phenotypeMap phenotypeMimNumber 609310 mimNumber 120436 phenotypeInheritance None phenotypicSeriesMimNumber 120435 phenotypeMappingKey 3 phenotype Colorectal cancer, hereditary nonpolyposis, type 2 phenotypeMappingKey 3 mimNumber 120436 phenotypeInheritance Autosomal recessive phenotype Mismatch repair cancer syndrome phenotypeMimNumber 276300 phenotypeMappingKey 3 mimNumber 120436 phenotypeInheritance Autosomal dominant phenotype Muir-Torre syndrome phenotypeMimNumber 158320 chromosomeLocationStart 37034840 chromosomeSort 132 chromosomeSymbol 3 mimNumber 120436 geneInheritance None confidence C mappingMethod Fd, A geneName mutL, E. coli, homolog of, 1 mouseMgiID MGI:101938 mouseGeneSymbol Mlh1 computedCytoLocation 3p22.2 cytoLocation 3p21.3 transcript uc003cgl.3 chromosomeLocationEnd 37092336 chromosome 3 contributors Ada Hamosh - updated : 05/01/2013 Ada Hamosh - updated : 4/29/2013 Cassandra L. Kniffin - updated : 4/22/2013 Cassandra L. Kniffin - updated : 4/3/2012 Anne M. Stumpf - updated : 3/14/2012 Cassandra L. Kniffin - updated : 1/9/2012 Ada Hamosh - updated : 12/15/2011 Cassandra L. Kniffin - updated : 12/3/2010 Cassandra L. Kniffin - updated : 11/29/2010 Cassandra L. Kniffin - updated : 6/7/2010 Cassandra L. Kniffin - updated : 6/17/2009 Cassandra L. Kniffin - updated : 2/18/2009 Cassandra L. Kniffin - updated : 1/22/2009 Cassandra L. Kniffin - updated : 6/19/2008 Cassandra L. Kniffin - updated : 2/4/2008 Cassandra L. Kniffin - updated : 1/7/2008 George E. Tiller - updated : 11/8/2007 George E. Tiller - updated : 4/5/2007 Victor A. McKusick - updated : 2/26/2007 Patricia A. Hartz - updated : 2/5/2007 Victor A. McKusick - updated : 10/27/2006 Victor A. McKusick - updated : 10/9/2006 Cassandra L. Kniffin - updated : 5/17/2006 Victor A. McKusick - updated : 3/15/2006 Victor A. McKusick - updated : 3/7/2006 Patricia A. Hartz - updated : 12/22/2005 Victor A. McKusick - updated : 7/5/2005 Matthew B. Gross - reorganized : 4/15/2005 Victor A. McKusick - updated : 3/3/2005 Marla J. F. O'Neill - updated : 8/27/2004 Victor A. McKusick - updated : 8/6/2004 Victor A. McKusick - updated : 7/7/2004 Victor A. McKusick - updated : 4/5/2004 Victor A. McKusick - updated : 1/12/2004 Victor A. McKusick - updated : 12/12/2003 Victor A. McKusick - updated : 10/16/2003 Victor A. McKusick - updated : 1/23/2003 Victor A. McKusick - updated : 1/8/2003 Victor A. McKusick - updated : 11/21/2002 Victor A. McKusick - updated : 10/8/2002 Victor A. McKusick - updated : 4/24/2002 Victor A. McKusick - updated : 3/19/2002 Paul Brennan - updated : 3/14/2002 George E. Tiller - updated : 1/30/2002 Deborah L. Stone - updated : 11/28/2001 Victor A. McKusick - updated : 10/23/2001 Victor A. McKusick - updated : 8/23/2001 Michael J. Wright - updated : 8/7/2001 Paul J. Converse - updated : 11/16/2000 Victor A. McKusick - updated : 12/6/1999 Victor A. McKusick - updated : 5/14/1999 Ada Hamosh - updated : 3/19/1999 Victor A. McKusick - updated : 2/22/1999 Victor A. McKusick - updated : 1/26/1999 Stylianos E. Antonarakis - updated : 12/3/1998 Victor A. McKusick - updated : 8/11/1998 Victor A. McKusick - updated : 7/29/1998 Victor A. McKusick - updated : 6/30/1998 Ada Hamosh - updated : 4/30/1998 Victor A. McKusick - updated : 9/8/1997 Victor A. McKusick - updated : 8/20/1997 Moyra Smith - updated : 7/1/1996 clinicalSynopsisExists false mimNumber 120436 allelicVariantList allelicVariant status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750198 text In a colorectal tumor cell line (H6) ({609310}) manifesting microsatellite instability, {54:Papadopoulos et al. (1994)} used a technique that involves the transcription and translation in vitro of PCR products to demonstrate that only a truncated polypeptide was produced. Sequence analysis of the cDNA revealed a C-to-A transversion at codon 252, resulting in the substitution of a stop codon for serine. No band at the normal C position was identified in the cDNA or genomic DNA from the H6 cells, indicating that these cells were devoid of a wildtype MLH1 allele. mutations MLH1, SER252TER number 1 clinvarAccessions RCV000018607;;1;;;RCV000130936;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63751109 text In a family with hereditary nonpolyposis colon cancer ({609310}), {11:Bronner et al. (1994)} found that 4 affected individuals were heterozygous for a C-to-T substitution in an exon encoding amino acids 41 to 69, which corresponds to a highly conserved region of the protein. The nucleotide substitution resulted in a ser44-to-phe amino acid change. mutations MLH1, SER44PHE number 2 clinvarAccessions RCV000075169;;3;;;RCV000018608;;1 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs63751247 text In a man with mismatch repair cancer syndrome ({276300}), {24:Hamilton et al. (1995)} identified a 3-bp deletion (AAG) in the MLH1 gene, resulting in the loss of a lysine at codon 618. The patient had adenocarcinomas of the ascending and transverse colon at the age of 30, adenomas of the descending and sigmoid colon at the ages of 32 and 33, and an ileal adenocarcinoma and a glioblastoma multiforme at the age of 33. There was a family history of HNPCC. The patient was also reported to have a transitional cell carcinoma of the ureter. mutations MLH1, 3-BP DEL, LYS618DEL number 3 clinvarAccessions RCV000075383;;3;;;RCV000018609;;1;;;RCV000129328;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text {50:Nystrom-Lahti et al. (1995)} found that a 3.5-kb genomic deletion in the MLH1 gene was responsible for 14 of 30 Finnish kindreds meeting international diagnostic criteria for HNPCC ({609310}). The origins of the families were clustered in the south-central region of Finland. The mutation consisted of exon 15 and the proximal 2.4 kb of intron 15 joined to a distal half of intron 16 followed by intron 17. Introns 15 and 16 were found to be rich in Alu repetitive sequences. Sequence analysis of the deletion breakpoint region in both mutant and normal alleles suggested to {50:Nystrom-Lahti et al. (1995)} that the deletion may have been due to recombination between 2 Alu repeat elements, 1 in intron 15 and another in intron 16. This large deletion mutation and the splice site mutation leading to deletion of exon 6 ({120436.0005}), referred to by {48:Moisio et al. (1996)} as mutations 1 and 2 respectively, are frequent among Finnish kindreds with HNPCC. In order to assess the ages and origins of these mutations, {48:Moisio et al. (1996)} constructed a map of 15 microsatellite markers around MLH1 and used this information and haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of markers encompassing 2.0 to 19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5 to 14 markers spanning 2.0 to 15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these 2 mutations. The analyses suggested to the authors that the spread of mutation 1 started 16 to 43 generations (400 to 1,075 years) ago and that of mutation 2 started 5 to 21 generations (125 to 525 years) ago. These datings were compatible with genealogic results identifying a common ancestor born in the 16th and 18th century, respectively. The results indicated to {48:Moisio et al. (1996)} that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 were the result of single ancestral founding mutations relatively recent in origin in the population. Alternatively, it is possible that the mutations arose elsewhere and were introduced into Finland more recently. mutations MLH1, 3.5-KB DEL number 4 clinvarAccessions RCV000018610;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text In 5 Finnish families with HNPCC ({609310}), {50:Nystrom-Lahti et al. (1995)} found that a splice site mutation in the MLH1 gene was responsible. The mutation consisted of a G-to-A transition in the -1 position of the splice acceptor site in intron 5. This resulted in deletion of the 92-bp segment corresponding to exon 6 and caused a frameshift that led to a premature stop codon 24-bp downstream. See also {48:Moisio et al. (1996)} and {120436.0004}. mutations MLH1, IVS5, G-A, -1 number 5 clinvarAccessions RCV000018611;;1 status live name MUIR-TORRE SYNDROME text Muir-Torre syndrome (MRTES; {158320}) is an autosomal dominant disorder characterized by development of sebaceous gland tumors and skin cancers, including keratoacanthomas and basal cell carcinomas. Affected family members may manifest a wide spectrum of internal malignancies, which include colorectal, endometrial, urologic, and upper gastrointestinal neoplasms. Sebaceous gland tumors, which are rare in the general population, are considered to be the hallmark of MRTES, and may arise prior to the development of other visceral cancers. Hereditary nonpolyposis colorectal cancer shares many features in common with MRTES, leading {43:Lynch et al. (1985)} to propose that these 2 syndromes have a common genetic basis. {6:Bapat et al. (1996)} found a mutation in MLH1 locus in a large, well-characterized kindred in which 17 affected family members had colorectal and endometrial cancers, sebaceous gland tumors, and hematopoietic malignancies. The family was originally reported by {22:Green et al. (1994)} who excluded linkage to the MSH2 locus ({609309}). {55:Paraf et al. (1995)} also described this family. {6:Bapat et al. (1996)} studied 2 affected sibs and found by a protein-truncation test (PTT) a truncated gene product of approximately 41 kD in addition to the expected wildtype MLH1 protein of 53.9 kD. Further analysis discovered a deletion of 370 bp (codons 346-467) corresponding to exon 12 of MLH1 cDNA. An examination of the MLH1 sequence indicated that deletion generated a frameshift resulting in a stop codon at nucleotides 1472-1474 in exon 13 and a truncated protein of 40.8 kD. Linkage analysis with an intragenic marker indicated that the affected parent was heterozygous and the unaffected parent homozygous for the wildtype allele. mutations MLH1, 370-BP DEL number 6 clinvarAccessions RCV000018612;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text In 5 of 21 Danish families with HNPCC ({609310}) satisfying the Amsterdam criteria, {31:Jager et al. (1997)} found a splice-donor mutation in intron 14 of MLH1: a combined 7-bp deletion and 4-bp insertion that led to the exchange of the obligatory thymidine at position +2 and the exchange of conserved purines at positions +3 to +5 in the splice donor site. Only 2 of 25 affected individuals suffered from extracolonic cancer. One patient had endometrial cancer by the age of 33 years and 3 successive colorectal cancers. The second patient had cancer of the ampulla of vater by the age of 54 years and 4 colorectal cancers. The phenotype in the families with the intron 14 mutation corresponded to Lynch syndrome I. In 4 families with other types of intronic and splice site mutations, almost 50% of affected individuals had extracolonic tumors corresponding to Lynch syndrome II. {31:Jager et al. (1997)} suggested that clinical surveillance could be restricted to colonic examinations in HNPCC gene carriers with monoallelic MLH1 expression. mutations MLH1, IVS14DS, 7-BP DEL AND 4-BP INS number 7 clinvarAccessions RCV000018613;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750710 text In a family that fulfilled the Amsterdam criteria of HNPCC ({609310}) ({72:Vasen et al., 1991}), {79:Wang et al. (1997)} identified a his329-to-pro germline mutation. That this mutation was of pathogenetic significance was proved by finding the same missense mutation as a somatic event ('second hit') in colonic tumors of 2 other HNPCC patients who had germline mutations at different sites of the MLH1 gene. mutations MLH1, HIS329PRO number 8 clinvarAccessions RCV000075954;;3;;;RCV000018614;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text In a French-Canadian kindred, {84:Yuan et al. (1998)} found that a novel truncating mutation, 1784delT, was associated with HNPCC ({609310}). The I1307K APC polymorphism ({175100.0029}) was also segregating in the family. This polymorphism, associated with an increased risk of colorectal cancer, had previously been identified only in individuals of self-reported Ashkenazi Jewish origin. In the French-Canadian family, there appeared to be no relationship between the I1307K polymorphism and the presence or absence of cancer. mutations MLH1, 1-BP DEL, 1784T number 9 clinvarAccessions RCV000018615;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63751615 text In a hereditary nonpolyposis colorectal cancer ({609310}) family from Turkey, {61:Ricciardone et al. (1999)} identified 3 sibs, born of consanguineous parents, who developed hematologic malignancy at a very early age, 2 of whom displayed signs of type I neurofibromatosis (NF1; {162200}). Sequence analysis in the 3 sibs demonstrated homozygosity for a 676C-T mutation in the MLH1 gene, leading to an arg226-to-ter mutation (R226X). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents had colon cancer at an early age. The phenotype in the sibs was consistent with the mismatch repair cancer syndrome ({276300}), which manifests features of NF1 and hematologic malignancies. {30:Huang et al. (2001)} studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that she was heterozygous for the R226X mutation. As this mutation is 2 bp from the 3-prime end of exon 8 and might affect donor splicing, an in vitro transcription translation assay was performed and confirmed the presence of the truncated peptide, which lacked the critical PMS2-binding regions at its C terminus. mutations MLH1, ARG226TER number 10 alternativeNames MISMATCH REPAIR CANCER SYNDROME, INCLUDED clinvarAccessions RCV000075801;;3;;;RCV000018616;;1;;;RCV000018617;;1;;;RCV000115485;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750206 text In 2 affected members of a consanguineous North African family in which 11 members of multiple generations developed colorectal cancers ({609310}), 8 of them before the age of 50 years, {76:Wang et al. (1999)} identified a heterozygous G-to-T transversion in exon 2 of the MLH1 gene, resulting in a gly67-to-trp (G67W) substitution. Two female children who were homozygous for the mutation had early onset of hematologic neoplastic disorders, including undifferentiated non-Hodgkin malignant lymphoma, acute myeloid leukemia, and a medulloblastoma, consistent with mismatch repair cancer syndrome ({276300}). In addition, both sisters had clinical features of type I neurofibromatosis (NF1; {162200}): one had multiple but strictly hemicorporal cafe-au-lait macules and a pseudarthrosis of the tibia, whereas the other had 9 cafe-au-lait spots. No other family member had NF1. mutations MLH1, GLY67TRP number 11 alternativeNames MISMATCH REPAIR CANCER SYNDROME, INCLUDED clinvarAccessions RCV000018618;;1;;;RCV000075475;;3;;;RCV000018619;;1 status live name RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE dbSnps rs35502531 text This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on the findings of {35:Kosinski et al. (2010)}. {42:Liu et al. (1999)} described 2 germline missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer ({609310}): lys618 to ala and glu578 to gly ({120436.0013}). The tumors did not show the usual DNA microsatellite instability (MSI) and would have been missed if this method was used for selection of patients for mutation screening. Using in vitro functional expression studies, {35:Kosinski et al. (2010)} demonstrated that the K618A variant was fully expressed and retained MMR activity, and that PMS2 ({600259}) was stable. The authors classified K618A as a variant of uncertain significance rather than as disease causing. mutations MLH1, LYS618ALA number 12 clinvarAccessions RCV000130907;;1;;;RCV000034542;;1;;;RCV000018620;;1;;;RCV000075382;;3;;;RCV000121363;;0;;;RCV000144600;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63751612 text See {120436.0012} and {42:Liu et al. (1999)}. mutations MLH1, GLU578GLY number 13 clinvarAccessions RCV000018621;;1;;;RCV000075342;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text {75:Vilkki et al. (2001)} identified a homozygous deletion of exon 16 of the MLH1 gene in a 4-year-old girl who died unexpectedly of brain hemorrhage caused by glioma. She also had cafe-au-lait spots, including multiple axillary freckles characteristic of NF1 (see {162200}) without other features of NF1. The phenotype in this girl was consistent with the spectrum of mismatch repair cancer syndrome ({276300}). Both parents, who had family histories of HNPCC ({609310}), were heterozygous for the deletion. mutations MLH1, EX16DEL number 14 alternativeNames MISMATCH REPAIR CANCER SYNDROME, INCLUDED clinvarAccessions RCV000018623;;1;;;RCV000018622;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text {17:Gazzoli et al. (2002)} examined 14 cases suspected to represent hereditary nonpolyposis colorectal carcinoma ({609310}) with microsatellite instability (MSI), but in which no germline MSH2 ({609309}), MSH6 ({600678}), or MLH1 mutations were detected, for hypermethylation of CpG sites in the critical promoter region of MLH1. The methylation patterns were determined using methylation-specific PCR and by sequence analysis of sodium bisulfite-treated genomic DNA. In 1 case, DNA hypermethylation of 1 allele was detected in DNA isolated from blood. In the tumor from this case, which showed high microsatellite instability, the unmethylated MLH1 allele was eliminated by loss of heterozygosity, and the methylated allele was retained. This biallelic inactivation resulted in loss of expression of MLH1 in the tumor as confirmed by immunohistochemistry. These results suggested a novel mode of germline inactivation of a cancer susceptibility gene. {49:Morak et al. (2008)} identified hypermethylation of the MLH1 proximal promoter region in peripheral blood cells of 12 (13%) of 94 unrelated patients with tumors and loss of MLH1 protein expression without mutations in the MLH1 gene. Normal colonic tissue, buccal mucosa, and tumor tissue available from 3 patients also showed abnormal methylation at the MLH1 promoter. Seven patients who were heterozygous for informative SNPs showed allele-specific methylation that was not restricted to either allelic variant. Five patients had about 50% methylation, consistent with complete methylation of 1 allele. One patient showed 100% methylation, and the rest showed mosaicism or incomplete methylation. Hypermethylation was found in 1 mother-son pair, suggesting familial predisposition for an epimutation. However, there was no evidence for epigenetic inheritance in the remaining families, and 6 patients showed a mosaic or incomplete methylation pattern, which argued against inheritance. {49:Morak et al. (2008)} concluded that MLH1 hypermethylation in normal body cells may constitute a pre-lesion, and that patients with such defects should be under surveillance. {14:Crepin et al. (2012)} identified constitutional MLH1 epimutations in 2 (1.5%) of 134 patients suspected of having Lynch syndrome who did not have germline mutations in the MMR genes. One patient was a man who developed colorectal cancer at age 35 years. Tumor tissue showed MSI, and analysis of lymphocyte DNA showed complete hypermethylation of the promoter of 1 MLH1 allele. The second patient was a woman with colorectal cancer, who had a son with colorectal cancer and 2 daughters with dysplastic colonic polyps. Blood from the mother showed 20% hypermethylation at the MLH1 promoter, suggesting mosaicism. The son and 1 affected daughter also showed partial hypermethylation in blood, suggesting transmission of the epimutation through the germline. Tumor tissue from the 3 patients in the second family also showed partial hypermethylation at MLH1, with loss of MLH1 expression in 2. Finally, tumor tissue from the daughter also carried a somatic BRAF mutation ({164757.0001}). mutations MLH1, HYPERMETHYLATION number 15 clinvarAccessions RCV000018624;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text {21:Green et al. (2003)} described, in a Newfoundland kindred, the first report of a heritable MLH1 promoter mutation in HNPCC ({609310}). The -42C-T mutation was within a putative Myb protooncogene ({189990}) binding site. Using electrophoretic mobility shift assays, they demonstrated that the mutated Myb binding sequence was less effective in binding nuclear proteins than the wildtype promoter sequence. Using in vivo transfection experiments in HeLa cells, they further demonstrated that the mutated promoter had only 37% of the activity of the wildtype promoter in driving the expression of a reporter gene. The average age of onset in 6 family members affected with colorectal cancer was 62 years, which is substantially later than the typical age of onset in HNPCC families. This finding was considered consistent with the substantial decrease, but not total elimination, of mismatch repair function in affected members of this kindred. mutations MLH1, -42, C-T number 16 clinvarAccessions RCV000018625;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750781 text The majority of mutations associated with HNPCC occur in the MSH2 ({609309}) and MLH1 genes (see {120435} and {609310}, respectively). {81:Wei et al. (2003)} studied these 2 genes in 15 Taiwanese HNPCC kindreds meeting the Amsterdam criteria, using both RNA- and DNA-based methods. In the 15 kindreds they found no MSH2 mutations and mutations in MLH1 in 3 kindreds (20%), which is lower than that reported in other countries. Two novel deletions were found and 1 mutation had been reported several times in western countries ({44:Maliaka et al., 1996}; {41:Liu et al., 1996}; {71:Trojan et al., 2002}). A C-to-T transition in codon 117 in exon 4 resulted in an amino acid change from threonine to methionine. mutations MLH1, THR117MET number 17 clinvarAccessions RCV000075666;;3;;;RCV000144599;;1;;;RCV000018626;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs121912962 text In 4 cases of hereditary nonpolyposis colorectal cancer ({609310}), {68:Taylor et al. (2003)} found deletion of 3 nucleotides: 1846-1848delAAG resulting in deletion of lys616 (K616del) from the MLH1 protein. This mutation had been previously observed by {47:Miyaki et al. (1995)}. {68:Taylor et al. (2003)} used the multiplex ligation-dependent probe amplification (MLDA) assay to demonstrate the deletion. {67:Tang et al. (2009)} identified a heterozygous 1846delAAG mutation in affected members of 5 Taiwanese families with HNPCC2. mutations MLH1, LYS616DEL number 18 clinvarAccessions RCV000018627;;1 status live name COLORECTAL CANCER, SPORADIC, SUSCEPTIBILITY TO dbSnps rs28930073 text Using a novel high density oligonucleotide array (HNPCC Chip) to look for variants in the MLH1, MSH2 ({609309}), and MSH6 ({600678}) genes in Israeli probands with familial colorectal cancer (CRC; {114500}) unstratified with respect to the microsatellite instability phenotype, {39:Lipkin et al. (2004)} identified a 415G-C translation in the MLH1 gene, resulting in an asp132-to-his (D132H) amino acid substitution. MLH1 415C conferred clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually did not have the microsatellite instability (MSI) defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 was attenuated, but not eliminated, by the MLH1 415G-C mutation. mutations MLH1, ASP132HIS number 19 clinvarAccessions RCV000115482;;2;;;RCV000018628;;1;;;RCV000075697;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750899 text In 8 affected members of a Danish family with HNPCC ({609310}) reported by {8:Bisgaard et al. (2002)}, {59:Raevaara et al. (2004)} identified a pro648-to-ser (P648S) mutation in the MLH1 gene. Only 1 member, a 6-year-old child with first-cousin parents, was homozygous for the mutation. She had mild features of type I neurofibromatosis ({162200}) and no hematologic cancers. She displayed cafe-au-lait spots and a skin tumor clinically diagnosed as a neurofibroma, but no axillary freckles or other abnormalities. The phenotype was consistent with the spectrum of mismatch repair cancer syndrome ({276300}). {59:Raevaara et al. (2004)} commented that the mutated protein was unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual were linked to shortage of the functional protein. mutations MLH1, PRO648SER number 20 alternativeNames MISMATCH REPAIR CANCER SYNDROME, INCLUDED clinvarAccessions RCV000018630;;1;;;RCV000018629;;1;;;RCV000075432;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750691 text In a 30-year-old patient who had developed colon cancer ({609310}) at the age of 22 years, {60:Rey et al. (2004)} identified a homozygous 806C-G transversion in exon 10 of the MLH1 gene, resulting in a ser269-to-thr (S269T) substitution. Many members of the paternal and maternal families presented with colon cancer, gastric polyposis, or breast cancer. A founder effect was proposed because both ancestral families originated from the same small region in the south of France. A complete MLH1 inactivation was thought to have been responsible for the precocity of colon cancer and the more aggressive phenotype in this patient. Relatives could not be studied. mutations MLH1, SER269TER number 21 clinvarAccessions RCV000075875;;3;;;RCV000018631;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750217 text In a screen of 226 patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria for MSH2 ({609309}) and MLH1 germline mutations, {36:Kurzawski et al. (2006)} found the ala681-to-thr (A681T) change of MLH1 in 8 Polish families, consistent with HNPCC2 ({609310}). They concluded that this, the most frequently occurring mutation of MLH1 in Poland, was a founder mutation. The amino acid substitution resulted from a 2041G-to-A transition in exon 18. mutations MLH1, ALA681THR number 22 clinvarAccessions RCV000075495;;3;;;RCV000018632;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text {46:McVety et al. (2006)} demonstrated the presence of an exon splicing enhancer (ESE) in exon 3 of MLH1 and showed that a 3-bp in-frame deletion (213_215delAGA) in this ESE was the cause of HNPCC ({609310}) in a Quebec family. The deletion resulted in loss of codon 71 and caused skipping of exon 3 during mRNA splicing. mutations MLH1, 3-BP DEL, 213AGA number 23 clinvarAccessions RCV000018633;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text In 4 unrelated patients with HNPCC ({609310}), {53:Pagenstecher et al. (2006)} identified a heterozygous 2103G-C transversion in the MLH1 gene. The change was predicted to result in a gln701-to-his (Q701H) substitution, but RNA analysis showed that it resulted in a splicing defect and complete loss of exon 18. mutations MLH1, EX18DEL number 24 clinvarAccessions RCV000018634;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans was provided by {66:Suter et al. (2004)} by the identification of individuals in whom 1 allele of the MLH1 gene was epigenetically silenced throughout the soma (implying a germline event). These individuals were affected by hereditary nonpolyposis colorectal cancer but did not have identifiable mutations in MLH1, even though it was silenced, which demonstrated that an epimutation can phenocopy a genetic disease. mutations MLH1, EPIGENETICALLY SILENCED number 25 clinvarAccessions RCV000018635;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs1800734 text {29:Hitchins et al. (2007)} described a family in which a 66-year-old woman, the mother of 3 sons by 2 different mates, had the clinical picture of hereditary nonpolyposis colorectal cancer. She had metachronous carcinomas that had microsatellite instability and lacked MLH1 expression. The diagnosis of cancer of the endometrium was made at the age of 45; of the colon, at age 59; and of the rectum at 60 years. She was heterozygous for a SNP within the MLH1 promoter ({dbSNP rs1800734}), with methylation confined to the A allele. In this woman methylation of the A allele on approximately 50% of chromosomes was confirmed by sulfite sequencing. {29:Hitchins et al. (2007)} identified an expressible C-T SNP within MLH1 exon 16 in her son, which was used to demonstrate that he was transcribing RNA only from the MLH1 allele inherited from his father. The data were consistent with transmission of the MLH1 epimutation from the proband to her son. In DNA from peripheral blood leukocytes obtained from this son, approximately half of the MLH1 alleles were methylated. In contrast, his sperm had no trace of MLH1 methylation, despite containing equal proportions of alleles derived from his father and mother. Furthermore, analysis of the RNA in his sperm at the MLH1 exon 16 C-T SNP showed reactivation of the maternally derived MLH1 allele. These results indicated reversion of the MLH1 epimutation to normality during spermatogenesis, suggesting a negligible risk of transmission from that family member. mutations MLH1, EPIGENETICALLY SILENCED INHERITED number 26 clinvarAccessions RCV000018636;;1 status live name MISMATCH REPAIR CANCER SYNDROME text In a 4-year-old boy with glioblastoma, nephroblastoma, and cafe-au-lait spots consistent with mismatch repair cancer syndrome ({276300}), {57:Poley et al. (2007)} identified compound heterozygosity for 2 mutations in the MLH1 gene: a 2-bp deletion (593delAG) and a met35-to-asn (M35N; {120436.0028}) substitution. Both tumors and normal tissue were negative for the MLH1 protein. The nephroblastoma showed microsatellite instability, but the glioblastoma did not. Both parents, who were each heterozygous for a respective mutation, came from families with HNPCC2 ({609310}). mutations MLH1, 2-BP DEL, 593AG number 27 alternativeNames COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, INCLUDED clinvarAccessions RCV000018637;;1;;;RCV000018638;;1 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs121912965 text See {120436.0027} and {57:Poley et al. (2007)}. mutations MLH1, MET35ASN number 28 alternativeNames COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, INCLUDED clinvarAccessions RCV000075101;;3;;;RCV000018640;;1;;;RCV000018639;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63749939 text In affected members of a family with HNPCC2 ({609310}), {13:Clyne et al. (2009)} identified a heterozygous 200G-A transition in exon 2 of the MLH1 gene, resulting in a gly67-to-glu (G67E) substitution. The male proband had breast cancer, leiomyosarcoma of the thigh, colon cancer, and prostate cancer. Other relatively unusual tumors in other affected family members included esophageal cancer, cervical adenosquamous carcinoma, oligodendroglioma, and prostate cancer. In vitro functional expression assays in yeast showed that the G67E-mutant protein interfered with the ability to prevent the accumulation of mutations, consistent with a loss of function. mutations MLH1, GLY67GLU number 29 clinvarAccessions RCV000132445;;1;;;RCV000075482;;3;;;RCV000018641;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63751194 text In affected members of 13 Taiwanese families with HNPCC2 ({609310}), {67:Tang et al. (2009)} identified a heterozygous 793C-T transition in exon 10 of the MLH1 gene, resulting in an arg265-to-cys (R265C) substitution. The mutation was not found in 300 controls. Cancers that occurred included colon, rectal, gastric, endometrial, ovarian, breast, and others. Haplotype analysis indicated 2 common haplotypes, 1 of which was shared by 10 families, suggesting a common origin in China several centuries ago. mutations MLH1, ARG265CYS number 30 clinvarAccessions RCV000034802;;1;;;RCV000022502;;1;;;RCV000075872;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 text In 14 unrelated patients and 95 family members among a series of 84 Lynch syndrome (see {609310}) families with germline mutations in MLH1, MSH2 ({609309}), or MSH6 ({600678}), {56:Pinheiro et al. (2011)} identified an identical exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 gene ({614043}). All 14 probands harbored an 11,627-bp deletion comprising exons 17 through 19 of the MLH1 gene and exons 26 through 29 of the LRRFIP2 gene. The 5-prime and 3-prime breakpoints were located 280 bp downstream of MLH1 exon 16 and 678 bp upstream of LRRFIP2 exon 25, respectively (Chr3: 37.089-37.101 Mb, GRCh37). The mutation was therefore designated 1896+280_oLRRFIP2:1750-678del. This mutation represented 17% of all deleterious mismatch repair mutations in their series. Haplotype analysis showed a conserved region of approximately 1 Mb, and the mutation age was estimated to be 283 +/- 78 years, or to the beginning of the 18th century. All 14 families originated from the Porto district countryside. {56:Pinheiro et al. (2011)} recommended using this mutation as first line screening for Lynch syndrome among families of Portuguese descent. mutations MLH1, 11.6-KB DEL number 31 clinvarAccessions RCV000022503;;1 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs267607735 text In 17 Spanish families originating from northern Spain with HNPCC2 ({609310}), {10:Borras et al. (2010)} identified a G-to-A transition in intron 3 of the MLH1 gene (306+5G-A). RT-PCR on patient lymphocytes showed an aberrant mRNA transcript expected to generate a truncated protein. This transcript was associated with an increased amount of a transcript corresponding to the in-frame skipping of exon 3. Although the variant is pathogenic at the RNA level, neither abnormal bands nor differences in protein expression were observed in lymphocytes from carriers, suggesting that the mutant protein was unstable. By age 70, the lifetime risk of colorectal cancer in carriers was estimated at 20.1% in men and 14.1% in women. A common haplotype was identified, consistent with a founder effect, and the age of the mutation was estimated to be from 53 to 122 generations. mutations MLH1, IVS3DS, G-A, +5 number 32 clinvarAccessions RCV000022504;;1;;;RCV000075634;;3 status live name COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2 dbSnps rs63750693 text In 12 Spanish families originating from southern Spain with HNPCC2 ({609310}), {10:Borras et al. (2010)} identified a 1865T-A transversion in the MLH1 gene, resulting in a leu622-to-his (L622H) substitution in a highly conserved residue at the interaction domain for MutL. In vitro functional expression studies showed that the substitution resulted in decreased amounts of the MLH1 protein. Five of 6 tumors analyzed lost the MLH1 wildtype allele, suggesting a growth advantage with loss of the wildtype protein. By age 70, the lifetime risk of colorectal cancer in carriers was estimated at 6.8% in men and 7.26% in women. A common haplotype was identified, consistent with a founder effect, and the age of the mutation was estimated to be from 12 to 22 generations. mutations MLH1, LEU622HIS number 33 clinvarAccessions RCV000075389;;3;;;RCV000022505;;1 status live name MISMATCH REPAIR CANCER SYNDROME dbSnps rs397514684 text In a boy with mismatch repair cancer syndrome ({276300}), {3:Baas et al. (2013)} identified a homozygous 218T-to-G transversion in exon 3 of the MLH1 gene, resulting in a leu73-to-arg (L73R) substitution. His parents were unrelated, but originated from the same Polynesian Pacific Island population. In vitro functional expression studies showed that the mutant protein had no DNA repair activity. The patient first presented with a glioblastoma multiforme and later developed a T-cell lymphoblastic lymphoma. He died of sepsis at the end of treatment. Brain imaging showed near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia. He was also noted to have multiple cafe-au-lait spots. The maternal family history was positive for colorectal cancer. mutations MLH1, LEU73ARG number 34 clinvarAccessions RCV000035016;;1 prefix * titles preferredTitle MutL, E. COLI, HOMOLOG OF, 1; MLH1 textSectionList textSection textSectionTitle Description textSectionContent MLH is homologous to the E. coli MutL gene and is involved in DNA mismatch repair. Heterozygous mutations in the MLH1 gene result in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; {609310}) ({54:Papadopoulos et al., 1994}). textSectionName description textSectionTitle Cloning textSectionContent After human homologs of the mutS gene of bacteria and yeast were found to have mutations responsible for hereditary nonpolyposis colorectal cancer (HNPCC1; {120435}), {54:Papadopoulos et al. (1994)} searched for other human mismatch repair (MMR) genes. A survey of EST databases derived from random cDNA clones revealed 3 additional human MMR genes, all related to the bacterial mutL gene. One of these genes was MLH1. The other 2 genes had a slightly greater similarity to the yeast mutL homolog PMS1 and were therefore denoted PMS1 ({600258}) and PMS2 ({600259}), respectively. {18:Genuardi et al. (1998)} characterized the normal alternative splicing of the MLH1 gene and reported a number of splice variants that exist in various tissue types. They observed splice variants lacking exons 6/9, 9, 9/10, 9/10/11, 10/11, 12, 16, and 17. The level of expression varied among different samples. All isoforms were found in 43 to 100% of the mononuclear blood cell samples, as well as in other tissues. The authors cautioned that knowledge of existence of multiple alternative splicing events not caused by genomic DNA changes is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis. textSectionName cloning textSectionTitle Gene Function textSectionContent Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the human MLH1 gene. {37:Li and Modrich (1995)} purified to near homogeneity an activity from HeLa cells that complemented H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the 8 base-base mismatches as well as a number of slipped-strand, insertion/deletion mispairs. The activity behaved as a single species during fractionation and copurified with proteins of 85 and 100 kD. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the human MLH1 product and the latter to the product of human PMS2 or a closely related gene. The 1:1 molar stoichiometry of the 2 polypeptides and their hydrodynamic behavior indicated formation of a heterodimer. These observations indicated that interactions between members of the family of the human MutL homologs may be restricted. {78:Wang et al. (2000)} used immunoprecipitation and mass spectrometry analyses to identify BRCA1 ({113705})-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM ({607585}), BLM ({604610}), MSH2 ({609309}), MSH6 ({600678}), MLH1, the RAD50 ({604040})-MRE11 ({600814})-NBS1 ({602667}) complex, and the RFC1 ({102579})-RFC2 ({600404})-RFC4 ({102577}) complex. {78:Wang et al. (2000)} suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. Meiotic recombination between homologous chromosomes generates crossover and noncrossover products, which are derived from the formation of double-strand breaks (DSBs) and result from distinct DSB repair pathways. {23:Guillon et al. (2005)} analyzed crossovers and noncrossovers in oogenesis and spermatogenesis in mice and determined that both crossover and noncrossover pathways were Spo11 ({605114}) dependent. Mlh1 was required for the formation of most crossovers, but not noncrossovers. The remaining 5 to 10% of crossover products did not require Mlh1. {23:Guillon et al. (2005)} concluded that the major crossover pathway requires MLH1 for crossover formation and for mismatch repair of heteroduplex DNA. MutL-alpha is a heterodimer of MLH1 and PMS2 that is required for mismatch repair. {32:Kadyrov et al. (2006)} identified human MutL-alpha as a latent endonuclease activated in a DNA mismatch-, MutS-alpha (see {609309})-, RFC-, PCNA ({176740})-, and ATP-dependent manner. Incision of a nicked heteroduplex by this 4-protein system was strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by 2 strand breaks was then removed by the 5-prime-to-3-prime activity of MutS-alpha-activated exonuclease-1 (EXO1; {606063}). By mutation analysis, {32:Kadyrov et al. (2006)} mapped the endonuclease active site to a conserved motif in PMS2. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent {5:Ban and Yang (1998)} determined the crystal structure of a 40-kD N-terminal fragment of E. coli MutL that retains all of the conserved residues in the MutL family. The structure of MutL is homologous to that of an ATPase-containing fragment of DNA gyrase. The authors demonstrated that MutL binds and hydrolyzes ATP to ADP and Pi. Mutations in the MutL family that cause deficiencies in DNA mismatch repair and a predisposition to cancer mainly occur in the putative ATP-binding site. {5:Ban and Yang (1998)} also provided evidence that the flexible, yet conserved loops surrounding this ATP-binding site undergo conformational changes upon ATP hydrolysis, thereby modulating interactions between MutL and other components of the repair machinery. {15:Ellison et al. (2001)} performed quantitative in vivo DNA mismatch repair (MMR) assays in the yeast S. cerevisiae to determine the functional significance of amino acid replacements in MLH1 and MSH2 genes observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. Three classes of missense codons were found: (i) complete loss of function, i.e., mutations; (ii) variants indistinguishable from wildtype protein, i.e., silent polymorphisms; and (iii) functional variants which supported MMR at reduced efficiency, i.e., efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The authors suggested that differences in the efficiency of DNA MMR may exist between individuals in the human population due to common polymorphisms. Using bioinformatic analysis, {35:Kosinski et al. (2010)} determined that the dimerization of MLH1 and PMS2 occurs via their C-terminal domains and involves residues 531 to 549 and 740 to 756 in MLH1 and residues 679 to 699 and 847 to 862 in PMS2. textSectionName biochemicalFeatures textSectionTitle Gene Structure textSectionContent {25:Han et al. (1995)} reported that the human MLH1 gene consists of 19 coding exons spanning approximately 100 kb. Exons 1 to 7 contain a region that is highly conserved in the MLH1 and PMS1 genes of yeast. textSectionName geneStructure textSectionTitle Mapping textSectionContent {54:Papadopoulos et al. (1994)} mapped the MLH1 gene to chromosome 3p21.3 by fluorescence in situ hybridization. {11:Bronner et al. (1994)} mapped the MLH1 gene to the same region, 3p23-p21.3, by fluorescence in situ hybridization. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent The mapping of MLH1 to 3p21 was of interest because markers in that area had been linked to hereditary nonpolyposis colon cancer in several families ({38:Lindblom et al., 1993}). Searching for mutations in the MLH1 gene, {54:Papadopoulos et al. (1994)} performed RT-PCR analyses of lymphoblastoid cell RNA and directly sequenced the coding region of the gene in 10 HNPCC kindreds linked to 3p markers. All affected individuals from 7 Finnish kindreds exhibited a heterozygous deletion of codons 578 to 632. The derivation of 5 of these 7 kindreds could be traced to a common ancestor, and the presence of the same presumptive defect in 2 other kindreds supported a 'founder effect' for many cases of HNPCC in the Finnish population. Codons 578 to 632 were found to constitute a single exon that was deleted from 1 allele in the 7 kindreds. This exon encodes several highly conserved amino acids found at identical positions in yeast MLH1. In another 3p-linked family, {54:Papadopoulos et al. (1994)} observed a 4-nucleotide deletion beginning at the first position of codon 727 and producing a frameshift with a new stop codon located 166 nucleotides downstream. As a result, the C-terminal 19 amino acids of MLH1 were substituted with 53 different amino acids, some encoded by nucleotides normally in the 3-prime untranslated region. Another kindred displayed a 4-nucleotide insertion between codons 755 and 756. This insertion resulted in a frameshift and extension of the open reading frame to include 99 nucleotides downstream of the normal stop codon. One cell line showed a transversion from TCA to TAA in codon 252, resulting in conversion of a serine to a stop ({120436.0001}). Simultaneously and independently, {11:Bronner et al. (1994)} likewise implicated the human MutL homolog, MLH1, in the form of HNPCC that maps to 3p. In 1 chromosome 3-linked HNPCC family, they demonstrated a missense mutation in affected individuals ({120436.0002}). Using PCR-SSCP analysis and DNA sequencing to examine the entire coding region of the MLH1 gene in DNAs of 34 unrelated cancer patients from HNPCC pedigrees, {25:Han et al. (1995)} found germline mutations in 8 (24%): 4 missense mutations, 1 intron mutation that would affect splicing, and 3 frameshift mutations resulting in truncation of the gene product downstream of the mutation site. {44:Maliaka et al. (1996)} identified 6 different novel mutations in the MLH1 and MSH2 genes in Russian and Moldavian HNPCC families. Three of these mutations occurred in CpG dinucleotides and led to a premature stop codon, splicing defect, or an amino acid substitution in evolutionarily conserved residues. Analysis of a compilation of published mutations including the new data suggested to the authors that CpG dinucleotides within the coding regions of the MSH2 and MLH1 genes are hotspots for single basepair substitutions. From a study of unrelated HNPCC families, {83:Wijnen et al. (1996)} commented that, whereas the spectrum of mutations at the MSH2 gene is heterogeneous, a cluster of MLH1 mutations were found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent MLH1 mutations described to date. They stated that their finding has great practical value in the design of clinical genetic services. By screening members of Finnish families displaying HNPCC for predisposing germline mutations in MSH2 and MLH1, {50:Nystrom-Lahti et al. (1995)} showed that 2 mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. One mutation, originally detected as a 165-bp deletion in MLH1 cDNA comprising exon 16, was shown to represent a 3.5-kb genomic deletion most likely resulting from Alu-mediated recombination ({120436.0004}). The second mutation destroyed the splice acceptor site of exon 6 ({120436.0005}). They commented that this was the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer. {50:Nystrom-Lahti et al. (1995)} designed a simple diagnostic test based on PCR for both mutations. Thus 2 ancestral founding mutations account for most Finnish HNPCC kindreds. {62:Sasaki et al. (1996)} studied 43 tumors and corresponding normal tissues from 23 Japanese patients with multiple primary cancers. They found no germline mutations of the MLH1 gene and detected only 2 somatic missense mutations among the 43 tumors examined. These 2 tumors had each shown increased replication error (RER+) at more than 1 of the 5 microsatellite loci examined. Only the second of these 2 mutations occurred in an evolutionarily conserved domain of the protein. {31:Jager et al. (1997)} reported studies based on the Danish HNPCC register comprising 28 families that fulfilled the Amsterdam criteria. They found an intron 14 founder mutation in the MLH1 gene ({120436.0007}) in approximately 25% of the kindreds and showed that it was associated with an attenuated HNPCC phenotype characterized by a highly reduced frequency of extracolonic tumors. The mutation was a combined 7-bp deletion and 4-bp insertion that 'silenced the mutated allele,' i.e., it was not expressed. Tumors exhibited microsatellite instability (MSI), and loss of the wildtype MLH1 allele was prevalent. {31:Jager et al. (1997)} proposed that the mutation resulted in a milder phenotype because the mutated MLH1 protein was prevented from exerting a dominant-negative effect on the concerted action of the mismatch repair system. {30:Huang et al. (2001)} studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that the proband was heterozygous for the R226X mutation ({120436.0011}). {63:Shimodaira et al. (1998)} described a new method for detecting mutations in MLH1 HNPCC using a dominant mutator effect of MLH1 cDNA expressed in Saccharomyces cerevisiae. Most MLH1 missense mutations identified in HNPCC patients abolish the dominant mutator effect. Furthermore, PCR amplification of MLH1 cDNA from mRNA of an HNPCC patient, followed by in vivo recombination into a gap expression vector, allowed detection of a heterozygous loss-of-function missense mutation in MLH1 using this method. This functional assay offers a simple method for detecting and evaluating pathogenic mutations in MLH1. {42:Liu et al. (1999)} described 2 missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer (see {120436.0012} and {120436.0013}). The tumors did not show MSI, raising some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations, and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggested that the mechanism involved in the carcinogenesis could be different from that generally hypothesized. In colorectal cancer arising in young Hong Kong Chinese, a high incidence of microsatellite instability and germline mismatch repair gene mutation has been found. Most of the germline mutations involve the MSH2 gene, which is different from the mutation spectrum in the Western population. In the MLH1 gene, alternative splicing is common, which complicates RNA-based mutation detection methods. In contrast, large deletions in MLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. {12:Chan et al. (2001)} reported the detection of a novel germline 1.8-kb deletion involving exon 11 of the MLH1 gene in a Hong Kong hereditary nonpolyposis colorectal cancer family. The mutation generated an mRNA transcript with deletion of exons 10 and 11, which is indistinguishable from one of the most common and predominant MLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggested that the 2 patients may share a common ancestral mutation. The results represented a caveat to investigators in the interpretation of alternative splicing and the important implications for the design of MLH1 mutation detection strategy in the Chinese population. The proband of one family developed colorectal cancer at the age of 33 years. The second patient with no family history of cancer developed colorectal cancer at the age of 38 years. {74:Viel et al. (2002)} examined a series of 52 patients belonging to HNPCC or HNPCC-related families, all of whom had previously tested negative for point mutations in MMR genes. Southern blot mutation screening of the MLH1 and MSH2 genes revealed abnormal restriction patterns in 3 patients who carried distinct MLH1 internal deletions. Although Alu repeats are likely to be implicated in most cases of such deletions, different molecular mechanisms may be involved. In particular, HNPCC resulting from L1-mediated recombination was identified by {74:Viel et al. (2002)} as another mechanism for MMR inactivating mutations. {19:Gorlov et al. (2003)} evaluated colocalization of pathogenic missense mutations (found in individuals with HNPCC) with high-score exonic splicing enhancer (ESE) motifs in the MSH2 and MLH1 genes. They found that pathogenic missense mutations in these genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a high propensity for splicing defects. In contrast, nonpathogenic missense mutations and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites showed that pathogenic effects of 20% or more of mutations in MSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of 16% or more of missense mutations in MLH1 genes are ESE related. Thus, the colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related. Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2, and MSH6 mutations underlie high penetrance CRC susceptibility in HNPCC, {39:Lipkin et al. (2004)} hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. They looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability phenotype. Association studies identified a new MLH1 variant (415G-C; {120436.0019}) in approximately 1.3% of Israeli CRC individuals self-described as Jewish, Christian, or Muslim. MLH1 415C conferred clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually did not have the microsatellite instability (MSI) defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-C mutation. These studies suggested that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than theretofore assumed. {51:Oliveira et al. (2004)} investigated KRAS ({190070}) in 158 HNPCC tumors from patients with germline MLH1, MSH2, or MSH6 mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H CRCs were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D ({190070.0003}) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02), or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. {51:Oliveira et al. (2004)} concluded that, depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status), and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway. {45:Mangold et al. (2004)} screened for mutations in the MSH2 and MLH1 genes in 41 unrelated index patients diagnosed with Muir-Torre syndrome (MRTES; {158320}), most of whom were preselected for mismatch repair deficiency in their tumor tissue. Germline mutations were identified in 27 patients (mutation detection rate of 66%). {45:Mangold et al. (2004)} noted that 25 (93%) of the mutations were located in MSH2, in contrast to HNPCC patients without the MRTES phenotype, in whom the proportions of MLH1 and MSH2 mutations are almost equal (p less than 0.001). {45:Mangold et al. (2004)} further noted that 6 (22%) of the mutation carriers did not meet the Bethesda criteria for HNPCC and suggested that sebaceous neoplasm be added to the HNPCC-specific malignancies in the Bethesda guidelines. {1:Alazzouzi et al. (2005)} studied the allelic distribution of microsatellite repeat bat26 in peripheral blood lymphocytes of 6 carriers and 4 noncarriers from 2 HNPCC families harboring germline MLH1 and MSH2 mutations, respectively. In noncarriers, there was a gaussian distribution with no bat26 alleles shorter than 21 adenine residues. All 6 MLH1/MSH2 mutation carriers showed unstable bat26 alleles (20 adenine residues or shorter) with an overall frequency of 5.6% (102 of 1814 clones detected). {1:Alazzouzi et al. (2005)} suggested that detection of short unstable bat26 alleles may assist in identifying asymptomatic carriers belonging to families with no detectable MMR gene mutations. {58:Quehenberger et al. (2005)} obtained estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease-causing mutations of the MSH2 and MLH1 genes. Families with known germline mutations of these genes were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for CRC and EC. The MSH2 and MHL1 loci were analyzed jointly as there was no significant difference in risk (p = 0.08). At age 70, CRC risk for men was 26.7% (95% CI, 12.6 to 51.0%) and for women, 22.4% (10.6 to 43.8%); the risk for EC was 31.5% (11.1 to 70.3%). These estimates of risk were considerably lower than ones previously used which did not account for the selection of families. Changes in the coding sequence, which may or may not affect the encoded protein sequence, may disrupt exon splicing enhancers (ESEs), leading to exon skipping. ESEs are short, degenerate, frequently purine-rich sequences that are important in both constitutive and alternative splicing. ESEs have been identified in a large number of genes, and their disruption has been linked to several genetic disorders, including HNPCC ({65:Stella et al., 2001}), cystic fibrosis ({219700}), Marfan syndrome ({154700}), and Becker muscular dystrophy ({300376}). {46:McVety et al. (2006)} studied a 3-bp deletion at the 5-prime end of exon 3 of MLH1 ({120436.0023}), resulting in deletion of exon 3 from RNA. Splicing assays suggested that the inclusion of exon 3 in mRNA was ESE-dependent. The exon 3 ESE was not recognized by all available motif-scoring matrices, highlighting the importance of RNA analysis in the detection of ESE-disrupting mutations. {53:Pagenstecher et al. (2006)} examined 19 variants in the MLH1 and MSH2 genes detected in patients with HNPCC for expression at the RNA level. Ten of the 19 were found to affect splicing, including several variants which were predicted to be missense mutations in exonic sequences (see, e.g., {120436.0024}). The findings suggested that mRNA examination of MLH1 and MSH2 mutations should precede functional tests at the protein levels. Without preselection and regardless of family history, {7:Barnetson et al. (2006)} recruited 870 patients under the age of 55 years soon after they received the diagnosis of colorectal cancer. They studied these patients for germline mutations in DNA mismatch-repair genes MLH1, MSH2 ({609309}), and MSH6 ({600678}) and developed a 2-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. Furthermore, they analyzed 2,938 patient-years of follow-up to determine whether genotype influenced survival. Among the 870 participants, 38 mutations were found: 15 in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6%) and women (3%) differed significantly (P less than 0.04). Survival among carriers was not significantly different from that among noncarriers. {69:Tournier et al. (2008)} examined potential splicing defects of 56 unclassified variants in the MLH1 gene and 31 in the MSH2 gene that were identified in 82 French patients with Lynch syndrome. The variants comprised 54 missense mutations, 10 synonymous changes, 20 intronic variants, and 3 single-codon deletions. The authors developed an ex vivo splicing assay by inserting PCR-amplified transcripts from patient genomic DNA into a reporter minigene that was transfected into HeLa cells. The ex vivo splicing assay showed that 22 of 85 variant alleles affected splicing, including 4 exonic variants that affected putative splicing regulatory elements. The study provided a tool for evaluating putative pathogenic effects of unclassified variants found in these genes. {67:Tang et al. (2009)} identified pathogenic mutations or deletions in the MLH1 or MSH2 gene in 61 (66%) of 93 Taiwanese families with HNPCC. Forty-two families had MLH1 mutations, including 13 with the R265C mutation ({120436.0030}) and 5 with a 3-bp deletion (1846delAAG; {120436.0018}). Thirteen of the MLH1 mutations were novel, and 6 large MLH1 deletions were also found. One family harbored MLH1 and MSH2 mutations. Using structural modeling, {35:Kosinski et al. (2010)} identified 19 different MLH1 alterations located in the C-terminal domain involved in dimerization with PMS2. Three changes, Q542L, L749P, and Y750X, caused decreased coexpression of PMS2, which was unstable in the absence of interaction with MLH1, suggesting that these 3 alterations interfered with MLH1-PMS2 dimerization. In vitro studies showed that all 3 changes compromised mismatch repair, suggesting that defects in dimerization can abrogate proper MLH1 function. Additional biochemical studies showed that 4 alterations with uncertain pathogenicity (A586P, L636P, T662P, and R755W), could be considered deleterious because of poor expression or poor MMR efficiency. Finally, some variants (e.g., K618A; {120436.0012}), which were previously classified as deleterious, were determined to have normal MMR activity. Constitutional Epigenetic Mutations, 'Germline Epimutation' {26:Herman et al. (1998)} reported that hypermethylation of the 5-prime CpG island of the MLH1 gene is found in most sporadic primary colorectal cancers with MSI and that this methylation was often, but not invariably, associated with loss of MLH1 protein expression. Such methylation also occurred, but was less prominent, in MSI-negative tumors, as well as in MSI-positive tumors with known mutations of a mismatch repair gene. No hypermethylation of MSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2-prime-deoxycytidine not only resulted in reexpression of MLH1 protein, but also in restoration of the mismatch repair capacity in MMR-deficient cell lines. The results suggested that MSI in sporadic colorectal cancer often results from epigenetic inactivation of MLH1 in association with DNA methylation. Germline defects in DNA mismatch repair genes account for the inherited familial cancer syndrome of hereditary nonpolyposis colon cancers in which affected individuals show accelerated development of cancers of the proximal colon, endometrium ({608089}), and stomach. These cancers typically demonstrate inactivation of the residual wildtype MMR allele inherited opposite the germline mutant, absence of DNA MMR activity in in vitro assays, and acquisition of an in vivo mutator phenotype showing up to 1,000-fold increased gene mutation rates. Additionally, these cancers display an associated instability of genomic MSI. MSI is similarly found in approximately 15 to 20% of sporadic colon cancers that arise in individuals without any family history of colon cancer. Like HNPCC-associated colon cancers, sporadic MSI colon cancers arise predominantly in the proximal colon and show a high rate of frameshift mutations at a mutation hotspot in the transforming growth factor-beta type II receptor tumor suppressor gene (TGFBR2; {190182}). Familial and sporadic MSI colon cancers thus appear to share a common carcinogenic pathway. {40:Liu et al. (1995)} established that MMR gene inactivation via somatic mutation was the cause of some cases of sporadic MSI colon cancers. However, unexpectedly, in many sporadic MSI colon cancers, MMR genes were found to remain wildtype. MMR coding sequences were similarly reported to be wildtype in many sporadic MSI endometrial cancers ({34:Katabuchi et al., 1995}). {33:Kane et al. (1997)} described methylation of the MLH1 promoter region in some MSI tumors. {73:Veigl et al. (1998)} investigated a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI-positive malignant tumors. In 5 of 6 such cases, they found that MLH1 protein was absent, even though MLH1-coding sequences were wildtype. In each case, absence of MLH1 protein was associated with the methylation of the MLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expression of the absent MLH1 protein. Moreover, in single cell clones, MLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of MLH1 additionally accounted for the silencing of both maternal and paternal tumor MLH1 alleles, both of which could be reactivated by 5-azacytidine. Thus, substantial numbers of human MSI cancers appear to arise by MLH1 silencing via an epigenetic mechanism that can inactivate both of the MLH1 alleles. Promoter methylation is intimately associated with this epigenetic silencing mechanism. Approximately 20% of endometrial cancers, the fifth most common cancer of women worldwide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors had remained elusive. {64:Simpkins et al. (1999)} investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors, on the other hand, there was evidence for limited methylation in only 1 of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that 2 MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggested that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer. {82:Wheeler et al. (2000)} studied 10 MSI-positive sporadic colorectal cancers and 10 colorectal cancers from individuals with HNPCC. The promoter region of the MLH1 gene was hypermethylated in 7 of the 10 MSI-positive sporadic cancers but in none of the HNPCC cancers. LOH at MLH1 was observed in 8 of the 10 HNPCC colorectal cancers. {82:Wheeler et al. (2000)} concluded that while the mutations and allelic loss are responsible for the MSI-positive phenotype in HNPCC cancers, the majority of MSI-positive sporadic cancers are hypermethylated in the promoter region of MLH1; therefore, tumors from HNPCC patients acquire a raised mutation rate through a different pathway than MSI-positive sporadic tumors. Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. {66:Suter et al. (2004)} hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. They reported 2 individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lacked evidence of genetic mutation in any mismatch repair gene but had had multiple primary tumors that showed mismatch repair deficiency, and both met clinical criteria for hereditary nonpolyposis colorectal cancer. {66:Suter et al. (2004)} reported methylation of the MLH1 promoter in a small proportion of FACS-sorted spermatozoa from an individual who harbored a soma-wide MLH1 epimutation. In an addendum to the report of {66:Suter et al. (2004)} and in a correspondence, {28:Hitchins and Ward (2007)} described reassessment of spermatozoa from the original individual using 2 quantitative techniques. They included methylation analysis of the imprinted control gene SNRPN ({182279}), which is unmethylated in spermatozoa cells. Their new data indicated that the MLH1 methylation previously reported in spermatozoa was most likely an artifact, attributable to a low level of contamination of the sample with either somatic cells or free DNA derived from somatic cells. These data altered the original interpretation that incomplete resetting of the epigenetic mark on MLH1 had occurred in a proportion of the individual's spermatozoa and suggested instead that reversal is complete in the actual gametes. Persons who have hypermethylation of 1 allele of MLH1 in somatic cells throughout the body (a germline epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the families of 2 such persons, {29:Hitchins et al. (2007)} found evidence that the epimutation was transmitted from a mother to her son but was erased in his spermatozoa. The affected maternal allele was inherited by 3 other sibs from these 2 families, but in those offspring the allele had reverted to the normal active state. These findings demonstrated a novel pattern of inheritance of cancer susceptibility and were consistent with transgenerational epigenetic inheritance. {20:Gosden and Feinberg (2007)} referred to genetics and epigenetics as 'nature's pen-and-pencil set.' They suggested that transmission of epimutations in MLH1 may have more general relevance than appears at first site. Perhaps it is rather common for disease to be caused by the failure of both the pen and pencil to write correctly. {9:Bjornsson et al. (2004)} suggested an integrated epigenetic and genetic approach to common human disease. The genetic and epigenetic model of common diseases--including neuropsychiatric and rheumatologic diseases and cancer--suggest that the epigenotype modulates genetic effects. The epigenotype, in turn, is affected by the environment, the epigenotype of the parents, age, and the genotype at loci that regulate DNA methylation and chromatin. {27:Hitchins and Ward (2009)} reviewed the etiologic role of constitutional MLH1 epimutations (see, e.g., {120436.0015}) in the development of HNPCC-related cancers. {14:Crepin et al. (2012)} identified constitutional MLH1 epimutations in 2 (1.5%) of 134 patients suspected of having Lynch syndrome who did not have germline mutations in the MMR genes. One patient was a man who developed colorectal cancer at age 35 years. Tumor tissue showed MSI, and analysis of lymphocyte DNA showed complete hypermethylation of the promoter of 1 MLH1 allele. The second patient was a woman with colorectal cancer, who had a son with colorectal cancer and 2 daughters with dysplastic colonic polyps. Blood from the mother showed 20% hypermethylation at the MLH1 promoter, suggesting mosaicism. The son and 1 affected daughter also showed partial hypermethylation in blood, suggesting transmission of the epimutation through the germline. Tumor tissue from the 3 patients in the second family also showed partial hypermethylation at MLH1, and tumor tissue from the daughter also carried a somatic BRAF mutation ({164757.0001}). {80:Ward et al. (2013)} screened 416 individuals with colorectal cancer showing loss of MLH1 expression but without deleterious germline mutations in MLH1. Constitutive DNA samples were screened for MLH1 methylation in all subjects and for promoter sequence changes in 357 individuals. Constitutional MLH1 epimutations were identified in 16 subjects. Of these, 7 (1.7%) had mono- or hemi-allelic methylation and 8 had low-level methylation (2%). {80:Ward et al. (2013)} concluded that although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer and suggested that screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor. Mismatch Repair Cancer Syndrome Mismatch repair cancer syndrome ({276300}), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome, results from biallelic mutations in the mismatch repair genes. The phenotype classically includes colorectal adenomas and brain tumors, most often glioblastoma. However, {70:Trimbath et al. (2001)} and {52:Ostergaard et al. (2005)} noted that the original definition may be too restrictive, and suggested that the full manifestation of biallelic mutations in MMR genes includes the additional findings of early-onset hematologic malignancies and cafe-au-lait spots suggestive of neurofibromatosis-1 (NF1; {162200}). {24:Hamilton et al. (1995)} identified a mutation in the MLH1 gene ({120436.0003}) in a patient with brain tumor-polyposis syndrome-1. He had hereditary nonpolyposis colon cancer, glioblastoma, and transitional cell carcinoma of the ureter. Tumor tissue samples showed DNA replication errors. {61:Ricciardone et al. (1999)} reported 3 sibs in an HNPCC family who developed hematologic malignancy at a very early age, 2 of whom displayed signs of NF1. DNA sequence analysis and allele-specific amplification in 2 of the sibs revealed a homozygous MLH1 mutation ({120436.0010}). {76:Wang et al. (1999)} described a typical HNPCC family in which MMR-deficient children who were homozygous for an MLH1 mutation ({120436.0011}) exhibited clinical features of de novo NF1 and early onset of extracolonic cancers. The observations demonstrated that MMR deficiency is compatible with human development but may lead to mutations during embryogenesis. Based on these observations, {76:Wang et al. (1999)} speculated that the NF1 gene is a preferential target for such alterations. {77:Wang et al. (2003)} demonstrated that somatic mutations of the NF1 gene occur more commonly in MMR-deficient cells. They observed NF1 alterations in 5 of 10 tumor cell lines with microsatellite instability compared to none of 5 MMR-proficient tumor cell lines. Somatic NF1 mutations were also detected in 2 primary tumors exhibiting microsatellite instability. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {4:Baker et al. (1996)} generated mice with a null mutation of the Mlh1 gene. They reported that in addition to compromising replication fidelity, Mlh1 deficiency appeared to cause both male and female sterility associated with reduced levels of chiasmata. Mlh1-deficient spermatocytes exhibited high levels of prematurely separated chromosomes and cell cycle arrest occurred in the first division of meiosis. {4:Baker et al. (1996)} also carried out analysis of the Mlh1 protein in spermatocytes and oocytes using immunostaining. They demonstrated that Mlh1 localizes at chiasma sites on meiotic chromosomes. They concluded that Mlh1 in the mouse is involved in both DNA mismatch repair and meiotic crossing over. Linkage maps constructed from genetic analysis of gene order and crossover frequency provide few clues to the basis of genomewide distribution of meiotic recombination which might point to variation in chromosome structure that influences meiotic recombination. To bridge that gap, {16:Froenicke et al. (2002)} generated a cytologic recombination map that identified individual autosomes in the male mouse. They prepared synaptonemal complex (SC) meiotic chromosome spreads from mouse spermatocytes, identified each autosome by multicolor FISH using chromosome-specific DNA libraries, and mapped more than 2,000 sites of recombination along individual autosomes, using immunolocalization of Mlh1, which as a mismatch repair protein marks crossover sites. They showed that SC length strongly correlated with crossover frequency and distribution. Although the length of most of these SCs corresponded to that predicted from their mitotic chromosome length rank, several SCs were longer or shorter than expected, with corresponding increases and decreases in Mlh1 frequency. Although all bivalents shared certain recombination features, such as few crossovers near the centromeres and a high rate of distal recombination, individual bivalents had unique patterns of crossover distribution along their length. In addition to SC length, other unidentified factors influenced crossover distribution, leading to hot regions on individual chromosomes with recombination frequencies as much as 6 times higher than average, as well as coldspots with no recombination. By reprobing the SC spreads with genetically mapped BACs, {16:Froenicke et al. (2002)} demonstrated a robust strategy for integrating genetic linkage and physical contig maps with mitotic and meiotic chromosome structure. {2:Avdievich et al. (2008)} generated transgenic mice with a G67R mutation in the Mlh1 gene located in 1 of the ATP-binding domains. Although cells derived from homozygous mice showed defects in DNA repair, the mutation did not affect the cellular response to DNA damage, including the apoptotic response of epithelial cells in the intestinal mucosa. The mice displayed a strong predisposition to cancer but developed significantly fewer intestinal tumors compared to Mlh1-null mice. Mlh1-null mice did show defects in the cellular response to DNA damage. These findings suggested that missense mutations in the Mlh1 gene may affect MMR tumor suppressor function in a tissue-specific manner. In addition, homozygous G67R mice were sterile due to the inability of the mutant protein to interact with meiotic chromosomes at pachynema, demonstrating that the ATPase activity of Mlh1 is essential for fertility in mammals. textSectionName animalModel geneMapExists true editHistory alopez : 05/01/2013 alopez : 4/29/2013 ckniffin : 4/22/2013 carol : 3/11/2013 terry : 8/17/2012 carol : 4/4/2012 terry : 4/4/2012 ckniffin : 4/3/2012 alopez : 3/14/2012 carol : 1/19/2012 ckniffin : 1/9/2012 alopez : 1/6/2012 terry : 12/15/2011 carol : 7/20/2011 wwang : 1/4/2011 ckniffin : 12/3/2010 wwang : 11/30/2010 ckniffin : 11/29/2010 wwang : 6/9/2010 ckniffin : 6/7/2010 ckniffin : 6/4/2010 wwang : 7/2/2009 ckniffin : 6/17/2009 wwang : 2/25/2009 ckniffin : 2/18/2009 wwang : 1/27/2009 ckniffin : 1/22/2009 wwang : 7/9/2008 ckniffin : 6/19/2008 wwang : 2/19/2008 ckniffin : 2/4/2008 carol : 1/15/2008 ckniffin : 1/7/2008 wwang : 11/28/2007 terry : 11/8/2007 carol : 9/6/2007 alopez : 4/13/2007 terry : 4/5/2007 alopez : 2/28/2007 terry : 2/26/2007 mgross : 2/5/2007 terry : 10/27/2006 alopez : 10/10/2006 carol : 10/9/2006 alopez : 6/23/2006 wwang : 5/17/2006 ckniffin : 5/17/2006 alopez : 3/15/2006 alopez : 3/13/2006 terry : 3/7/2006 wwang : 1/24/2006 wwang : 12/22/2005 terry : 12/21/2005 terry : 8/3/2005 alopez : 7/14/2005 wwang : 7/13/2005 wwang : 7/6/2005 terry : 7/5/2005 mgross : 4/15/2005 mgross : 4/15/2005 tkritzer : 3/11/2005 terry : 3/3/2005 carol : 9/30/2004 carol : 9/1/2004 carol : 9/1/2004 terry : 8/27/2004 carol : 8/20/2004 carol : 8/20/2004 ckniffin : 8/20/2004 tkritzer : 8/11/2004 terry : 8/6/2004 alopez : 7/12/2004 terry : 7/7/2004 alopez : 5/3/2004 alopez : 4/6/2004 terry : 4/5/2004 joanna : 3/17/2004 cwells : 1/14/2004 terry : 1/12/2004 cwells : 12/17/2003 terry : 12/12/2003 terry : 11/11/2003 cwells : 10/21/2003 terry : 10/16/2003 alopez : 9/30/2003 tkritzer : 9/15/2003 ckniffin : 3/11/2003 carol : 1/29/2003 tkritzer : 1/27/2003 terry : 1/23/2003 tkritzer : 1/9/2003 terry : 1/8/2003 tkritzer : 11/25/2002 terry : 11/21/2002 carol : 10/16/2002 tkritzer : 10/14/2002 terry : 10/8/2002 terry : 6/27/2002 alopez : 5/7/2002 terry : 4/24/2002 terry : 4/4/2002 cwells : 4/3/2002 terry : 3/19/2002 alopez : 3/14/2002 cwells : 2/5/2002 cwells : 1/30/2002 carol : 1/24/2002 mcapotos : 12/21/2001 carol : 11/28/2001 terry : 11/15/2001 carol : 11/5/2001 mcapotos : 10/29/2001 terry : 10/23/2001 mcapotos : 8/29/2001 mcapotos : 8/23/2001 cwells : 8/16/2001 cwells : 8/9/2001 terry : 8/7/2001 cwells : 6/20/2001 cwells : 6/19/2001 joanna : 1/17/2001 mgross : 11/16/2000 carol : 3/30/2000 yemi : 2/18/2000 mgross : 12/9/1999 terry : 12/6/1999 mgross : 5/27/1999 mgross : 5/20/1999 terry : 5/14/1999 alopez : 3/19/1999 mgross : 2/25/1999 carol : 2/25/1999 mgross : 2/23/1999 terry : 2/22/1999 carol : 1/26/1999 carol : 12/3/1998 carol : 10/14/1998 dkim : 9/11/1998 dkim : 9/11/1998 dkim : 9/10/1998 dkim : 9/10/1998 carol : 8/19/1998 terry : 8/11/1998 alopez : 7/31/1998 alopez : 7/30/1998 alopez : 7/30/1998 terry : 7/29/1998 terry : 7/24/1998 alopez : 7/6/1998 terry : 6/30/1998 alopez : 5/14/1998 alopez : 5/11/1998 alopez : 5/11/1998 alopez : 5/11/1998 dholmes : 5/11/1998 jenny : 10/28/1997 terry : 10/27/1997 mark : 9/22/1997 jenny : 9/18/1997 terry : 9/8/1997 dholmes : 8/29/1997 jenny : 8/22/1997 terry : 8/20/1997 alopez : 3/19/1997 terry : 1/16/1997 jamie : 1/15/1997 terry : 1/7/1997 jamie : 11/15/1996 terry : 11/14/1996 terry : 10/8/1996 terry : 8/19/1996 terry : 7/29/1996 terry : 7/2/1996 terry : 7/2/1996 mark : 7/1/1996 terry : 7/1/1996 mark : 7/1/1996 terry : 6/27/1996 mark : 5/15/1996 terry : 5/13/1996 mark : 2/23/1996 terry : 2/19/1996 mark : 2/16/1996 mark : 2/13/1996 mark : 2/10/1996 terry : 2/5/1996 terry : 6/3/1995 mark : 5/14/1995 carol : 12/30/1994 jason : 7/13/1994 mimadm : 6/25/1994 carol : 12/9/1993 dateCreated Thu, 09 Dec 1993 03:00:00 EST creationDate Victor A. McKusick : 12/9/1993 epochUpdated 1367391600 dateUpdated Wed, 01 May 2013 03:00:00 EDT referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15563510 publisherName HighWire Press title Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. mimNumber 120436 referenceNumber 1 publisherAbbreviation HighWire pubmedID 15563510 source Hum. Molec. Genet. 14: 235-239, 2005. authors Alazzouzi, H., Domingo, E., Gonzalez, S., Blanco, I., Armengol, M., Espin, E., Plaja, A., Schwartz, S., Capella, G., Schwartz, S., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18337503 publisherName HighWire Press title Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis. mimNumber 120436 referenceNumber 2 publisherAbbreviation HighWire pubmedID 18337503 source Proc. Nat. Acad. Sci. 105: 4247-4252, 2008. authors Avdievich, E., Reiss, C., Scherer, S. J., Zhang, Y., Maier, S. M., Jin, B., Hou, H., Jr., Rosenwald, A., Riedmiller, H., Kucherlapati, R., Cohen, P. E., Edelmann, W., Kneitz, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ejhg.2012.117 publisherName Nature Publishing Group title Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome. mimNumber 120436 referenceNumber 3 publisherAbbreviation NPG pubmedID 22692065 source Europ. J. Hum. Genet. 21: 55-61, 2013. authors Baas, A. F., Gabbett, M., Rimac, M., Kansikas, M., Raphael, M., Nievelstein, R. A. J., Nicholls, W., Offerhaus, J., Bodmer, D., Wernstedt, A., Krabichler, B., Strasser, U., Nystrom, M., Zschocke, J., Robertson, S. P., van Haelst, M. M., Wimmer, K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0796-336 publisherName Nature Publishing Group title Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. mimNumber 120436 referenceNumber 4 publisherAbbreviation NPG pubmedID 8673133 source Nature Genet. 13: 336-342, 1996. authors Baker, S. M., Plug, A. W., Prolla, T. A., Bronner, C. E., Harris, A. C., Yao, X., Christie, D.-M., Monell, C., Arnheim, N., Bradley, A., Ashley, T., Liskay, R. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)81621-9 publisherName Elsevier Science title Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. mimNumber 120436 referenceNumber 5 publisherAbbreviation ES pubmedID 9827806 source Cell 95: 541-552, 1998. authors Ban, C., Yang, W. pubmedImages false publisherUrl http://www.elsevier.com/ title The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. (Letter) mimNumber 120436 referenceNumber 6 pubmedID 8751876 source Am. J. Hum. Genet. 59: 736-739, 1996. authors Bapat, B., Xia, L., Madlensky, L., Mitri, A., Tonin, P., Narod, S. 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C., Myrhoj, T., Bernstein, I., Nielsen, F. C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S016895250400160X publisherName Elsevier Science title An integrated epigenetic and genetic approach to common human disease. mimNumber 120436 referenceNumber 9 publisherAbbreviation ES pubmedID 15262407 source Trends Genet. 20: 350-358, 2004. authors Bjornsson, H. T., Fallin, M. D., Feinberg, A. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=20858721 publisherName HighWire Press title MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. mimNumber 120436 referenceNumber 10 publisherAbbreviation HighWire pubmedID 20858721 source Cancer Res. 70: 7379-7391, 2010. authors Borras, A., Pineda, M., Blanco, I., Jewett, E. M., Wang, F., Teule, A., Caldes, T., Urioste, M., Martinez-Bouzas, C., Brunet, J., Balmana, J., Torres, A., {and 13 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/368258a0 publisherName Nature Publishing Group title Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. mimNumber 120436 referenceNumber 11 publisherAbbreviation NPG pubmedID 8145827 source Nature 368: 258-261, 1994. authors Bronner, C. E., Baker, S. M., Morrison, P. T., Warren, G., Smith, L. G., Lescoe, M. K., Kane, M., Earabino, C., Lipford, J., Lindblom, A., Tannergard, P., Bollag, R. J., Godwin, A. R., Ward, D. C., Nordenskjold, M., Fishel, R., Kolodner, R., Liskay, R. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.onc.1204376 publisherName Nature Publishing Group title A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population. mimNumber 120436 referenceNumber 12 publisherAbbreviation NPG pubmedID 11420710 source Oncogene 20: 2976-2981, 2001. authors Chan, T. L., Yuen, S. T., Ho, J. W. C., Chan, A. S. Y., Kwan, K., Chung, L. P., Lam, P. W. Y., Tse, C. W., Leung, S. Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.bjc.6604860 publisherName Nature Publishing Group title The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome. mimNumber 120436 referenceNumber 13 publisherAbbreviation NPG pubmedID 19142183 source Brit. J. Cancer 100: 376-380, 2009. authors Clyne, M., Offman, J., Shanley, S., Virgo, J. D., Radulovic, M., Wang, Y., Ardern-Jones, A., Eeles, R., Hoffmann, E., Yu, V. P. C. C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/humu.21617 publisherName John Wiley & Sons, Inc. title Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. mimNumber 120436 referenceNumber 14 publisherAbbreviation Wiley pubmedID 21953887 source Hum. Mutat. 33: 180-188, 2012. authors Crepin, M., Dieu, M.-C., Lejeune, S., Escande, F., Boidin, D., Porchet, N., Morin, G., Manouvrier, S., Mathieu, M., Buisine, M.-P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11555625 publisherName HighWire Press title Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. mimNumber 120436 referenceNumber 15 publisherAbbreviation HighWire pubmedID 11555625 source Hum. Molec. Genet. 10: 1889-1900, 2001. authors Ellison, A. R., Lofing, J., Bitter, G. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60857-X publisherName Elsevier Science title Male mouse recombination maps for each autosome identified by chromosome painting. mimNumber 120436 referenceNumber 16 publisherAbbreviation ES pubmedID 12432495 source Am. J. Hum. Genet. 71: 1353-1368, 2002. authors Froenicke, L., Anderson, L. K., Wienberg, J., Ashley, T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12124320 publisherName HighWire Press title A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. mimNumber 120436 referenceNumber 17 publisherAbbreviation HighWire pubmedID 12124320 source Cancer Res. 62: 3925-3928, 2002. authors Gazzoli, I., Loda, M., Garber, J., Syngal, S., Kolodner, R. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/8102001/81020015.htm publisherName Springer title Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. mimNumber 120436 referenceNumber 18 publisherAbbreviation Springer pubmedID 9490293 source Hum. Genet. 102: 15-20, 1998. authors Genuardi, M., Viel, A., Bonora, D., Capozzi, E., Bellacosa, A., Leonardi, F., Valle, R., Ventura, A., Pedroni, M., Boiocchi, M., Neri, G. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61977-6 publisherName Elsevier Science title Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers. mimNumber 120436 referenceNumber 19 publisherAbbreviation ES pubmedID 14526391 source Am. J. Hum. Genet. 73: 1157-1161, 2003. authors Gorlov, I. P., Gorlova, O. Y., Frazier, M. L., Amos, C. I. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMe068284?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Genetics and epigenetics--nature's pen and-pencil set. (Editorial) mimNumber 120436 referenceNumber 20 publisherAbbreviation ATYPON pubmedID 17301306 source New Eng. J. Med. 356: 731-733, 2007. authors Gosden, R. G., Feinberg, A. P. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2003&volume=64&issue=3&spage=220 publisherName Blackwell Publishing title Germline hMLH1 promoter mutation in a Newfoundland HNPCC kindred. mimNumber 120436 referenceNumber 21 publisherAbbreviation Blackwell pubmedID 12919137 source Clin. Genet. 64: 220-227, 2003. authors Green, R. C., Green, A. G., Simms, M., Pater, A., Robb, J. D., Green, J. S. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Khandjian, E. W.; Rousseau, F. : Hereditary nonpolyposis colon cancer: analysis of linkage to 2p15-16 places the COCA1 locus telomeric to D2S123 and reveals genetic heterogeneity in seven Canadian families. mimNumber 120436 referenceNumber 22 pubmedID 8198129 source Am. J. Hum. Genet. 54: 1067-1077, 1994. authors Green, R. C., Narod, S. A., Morasse, J., Young, T. L., Cox, J., Fitzgerald, G. W. N., Tonin, P., Ginsburg, O., Miller, S., Poitras, P., Laframboise, R., Routhier, G., Plante, M., Morissette, J., Weissenbach, J. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(05)01642-4 publisherName Elsevier Science title Crossover and noncrossover pathways in mouse meiosis. mimNumber 120436 referenceNumber 23 publisherAbbreviation ES pubmedID 16307920 source Molec. Cell 20: 563-573, 2005. authors Guillon, H., Baudat, F., Grey, C., Liskay, R. M., de Massy, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199503303321302?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title The molecular basis of Turcot's syndrome. mimNumber 120436 referenceNumber 24 publisherAbbreviation ATYPON pubmedID 7661930 source New Eng. J. Med. 332: 839-847, 1995. authors Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7757073 publisherName HighWire Press title Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC). mimNumber 120436 referenceNumber 25 publisherAbbreviation HighWire pubmedID 7757073 source Hum. Molec. Genet. 4: 237-242, 1995. Note: Erratum: Hum. Molec. Genet. 9: 321 only, 2000. authors Han, H.-J., Maruyama, M., Baba, S., Park, J.-G., Nakamura, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9618505 publisherName HighWire Press title Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. mimNumber 120436 referenceNumber 26 publisherAbbreviation HighWire pubmedID 9618505 source Proc. Nat. Acad. Sci. 95: 6870-6875, 1998. authors Herman, J. G., Umar, A., Polyak, K., Graff, J. R., Ahuja, N., Issa, J.-P. J., Markowitz, S., Willson, J. K. V., Hamilton, S. R., Kinzler, K. W., Kane, M. F., Kolodner, R. D., Vogelstein, B., Kunkel, T. A., Baylin, S. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=19564652 publisherName HighWire Press title Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. mimNumber 120436 referenceNumber 27 publisherAbbreviation HighWire pubmedID 19564652 source J. Med. Genet. 46: 793-802, 2009. authors Hitchins, M. P., Ward, R. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1107-1289 publisherName Nature Publishing Group title Erasure of MLH1 methylation in spermatozoa--implications for epigenetic inheritance. mimNumber 120436 referenceNumber 28 publisherAbbreviation NPG pubmedID 17968340 source Nature Genet. 39: 1289 only, 2007. authors Hitchins, M. P., Ward, R. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa064522?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Inheritance of a cancer-associated MLH1 germ-line epimutation. mimNumber 120436 referenceNumber 29 publisherAbbreviation ATYPON pubmedID 17301300 source New Eng. J. Med. 356: 697-705, 2007. authors Hitchins, M. P., Wong, J. J. L., Suthers, G., Suter, C. M., Martin, D. I. K., Hawkins, N. J., Ward, R. L. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(01)90057-5 publisherName Elsevier Science title Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer. mimNumber 120436 referenceNumber 30 publisherAbbreviation ES pubmedID 11343035 source J. Pediat. 138: 629-635, 2001. authors Huang, S. C., Lavine, J. E., Boland, P. S., Newbury, R. O., Kolodner, R., Pham, T.-T. T., Arnold, C. N., Boland, C. R., Carethers, J. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)64284-0 publisherName Elsevier Science title Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression. mimNumber 120436 referenceNumber 31 publisherAbbreviation ES pubmedID 9245993 source Am. J. Hum. Genet. 61: 129-138, 1997. authors Jager, A. C., Bisgaard, M. L., Myrhoj, T., Bernstein, I., Rehfeld, J. F., Nielsen, F. C. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(06)00812-9 publisherName Elsevier Science title Endonucleolytic function of MutL-alpha in human mismatch repair. mimNumber 120436 referenceNumber 32 publisherAbbreviation ES pubmedID 16873062 source Cell 126: 297-308, 2006. authors Kadyrov, F. A., Dzantiev, L., Constantin, N., Modrich, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9041175 publisherName HighWire Press title Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. mimNumber 120436 referenceNumber 33 publisherAbbreviation HighWire pubmedID 9041175 source Cancer Res. 57: 808-811, 1997. authors Kane, M. F., Loda, M., Gaida, G. M., Lipman, J., Mishra, R., Goldman, H., Jessup, J. M., Kolodner, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=7585634 publisherName HighWire Press title Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. mimNumber 120436 referenceNumber 34 publisherAbbreviation HighWire pubmedID 7585634 source Cancer Res. 55: 5556-5560, 1995. authors Katabuchi, H., van Rees, B., Lambers, A. R., Ronnett, B. M., Blazes, M. S., Leach, F. S., Cho, K. R., Hedrick, L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.21301 publisherName John Wiley & Sons, Inc. title Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. mimNumber 120436 referenceNumber 35 publisherAbbreviation Wiley pubmedID 20533529 source Hum. Mutat. 31: 975-982, 2010. authors Kosinski, J., Hinrichsen, I., Bujnicki, J. M., Friedhoff, P., Plotz, G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2006&volume=69&issue=1&spage=40 publisherName Blackwell Publishing title Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). mimNumber 120436 referenceNumber 36 publisherAbbreviation Blackwell pubmedID 16451135 source Clin. Genet. 69: 40-47, 2006. authors Kurzawski, G., Suchy, J., Lener, M., Klujszo-Grabowska, E., Kladny, J., Safranow, K., Jakubowska, K., Jakubowska, A., Huzarski, T., Byrski, T., Debniak, T., Cybulski, C., {and 30 others} pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7892206 publisherName HighWire Press title Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. mimNumber 120436 referenceNumber 37 publisherAbbreviation HighWire pubmedID 7892206 source Proc. Nat. Acad. Sci. 92: 1950-1954, 1995. authors Li, G.-M., Modrich, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1193-279 publisherName Nature Publishing Group title Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. mimNumber 120436 referenceNumber 38 publisherAbbreviation NPG pubmedID 7903889 source Nature Genet. 5: 279-282, 1993. authors Lindblom, A., Tannergard, P., Werelius, B., Nordenskjold, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1374 publisherName Nature Publishing Group title The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. mimNumber 120436 referenceNumber 39 publisherAbbreviation NPG pubmedID 15184898 source Nature Genet. 36: 694-699, 2004. authors Lipkin, S. M., Rozek, L. S., Rennert, G., Yang, W., Chen, P.-C., Hacia, J., Hunt, N., Shin, B., Fodor, S., Kokoris, M., Greenson, J. K., Fearon, E., Lynch, H., Collins, F., Gruber, S. B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0195-48 publisherName Nature Publishing Group title Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. mimNumber 120436 referenceNumber 40 publisherAbbreviation NPG pubmedID 7704024 source Nature Genet. 9: 48-55, 1995. authors Liu, B., Nicolaides, N. C., Markowitz, S., Willson, J. K. V., Parsons, R. E., Jen, J., de la Chapelle, A., Hamilton, S. R., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://www.nature.com title Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. mimNumber 120436 referenceNumber 41 pubmedID 8574961 source Nature Med. 2: 169-174, 1996. authors Liu, B., Parsons, R., Papadopoulos, N., Nicolaides, N. C., Lynch, H. T., Watson, P., Jass, J. R., Dunlop, M., Wyllie, A., Peltomaki, P., de la Chapelle, A., Hamilton, S. R., Vogelstein, B., Kinzler, K. W. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/9105005/91050437.htm publisherName Springer title Missense mutations in hMLH1 associated with colorectal cancer. mimNumber 120436 referenceNumber 42 publisherAbbreviation Springer pubmedID 10598809 source Hum. Genet. 105: 437-441, 1999. authors Liu, T., Tannergard, P., Hackman, P., Rubio, C., Kressner, U., Lindmark, G., Hellgren, D., Lambert, B., Lindblom, A. pubmedImages false publisherUrl http://www.springeronline.com/ title Muir-Torre syndrome in several members of a family with a variant of the cancer family syndrome. mimNumber 120436 referenceNumber 43 pubmedID 4063166 source Brit. J. Derm. 113: 295-301, 1985. authors Lynch, H. T., Fusaro, R. M., Roberts, L., Voorhees, G. J., Lynch, J. F. pubmedImages false articleUrl http://link.springer.de/link/service/journals/00439/bibs/6097002/60970251.htm publisherName Springer title CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. mimNumber 120436 referenceNumber 44 publisherAbbreviation Springer pubmedID 8566964 source Hum. Genet. 97: 251-255, 1996. authors Maliaka, Y. K., Chudina, A. P., Belev, N. F., Alday, P., Bochkov, N. P., Buerstedde, J.-M. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15235030 publisherName HighWire Press title A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. (Letter) mimNumber 120436 referenceNumber 45 publisherAbbreviation HighWire pubmedID 15235030 source J. Med. Genet. 41: 567-572, 2004. authors Mangold, E., Pagenstecher, C., Leister, M., Mathiak, M., Rutten, A., Friedl, W., Propping, P., Ruzicka, T., Kruse, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15923275 publisherName HighWire Press title Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family. (Letter) mimNumber 120436 referenceNumber 46 publisherAbbreviation HighWire pubmedID 15923275 source J. Med. Genet. 43: 153-156, 2006. authors McVety, S., Li, L., Gordon, P. H., Chong, G., Foulkes, W. D. pubmedImages false publisherUrl http://highwire.stanford.edu title Germline mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. mimNumber 120436 referenceNumber 47 pubmedID 8581513 source J. Molec. Med. 73: 515-520, 1995. authors Miyaki, M., Konishi, M., Muraoka, M., Kikuchi-Yanoshita, R., Tanaka, K., Iwama, T., Mori, T., Koike, M., Ushio, K., Chiba, M., Nomizu, S., Utsunomiya, J. pubmedImages false title Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. mimNumber 120436 referenceNumber 48 pubmedID 8940269 source Am. J. Hum. Genet. 59: 1243-1251, 1996. authors Moisio, A.-L., Sistonen, P., Weissenbach, J., de la Chapelle, A., Peltomaki, P. pubmedImages false articleUrl http://dx.doi.org/10.1038/ejhg.2008.25 publisherName Nature Publishing Group title Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. mimNumber 120436 referenceNumber 49 publisherAbbreviation NPG pubmedID 18301449 source Europ. J. Hum. Genet. 16: 804-811, 2008. authors Morak, M., Schackert, H. K., Rahner, N., Betz, B., Ebert, M., Walldorf, C., Royer-Pokora, B., Schulmann, K., von Knebel-Doeberitz, M., Dietmaier, W., Keller, G., Kerker, B., Leitner, G., Holinski-Feder, E. pubmedImages false publisherUrl http://www.nature.com title Founding mutations and Alu-mediated recombination in hereditary colon cancer. mimNumber 120436 referenceNumber 50 pubmedID 7584997 source Nature Med. 1: 1203-1206, 1995. authors Nystrom-Lahti, M., Kristo, P., Nicolaides, N. C., Chang, S.-Y., Aaltonen, L. A., Moisio, A.-L., Jarvinen, H. J., Mecklin, J.-P., Kinzler, K. W., Vogelstein, B., de la Chapelle, A., Peltomaki, P. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15294875 publisherName HighWire Press title Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. mimNumber 120436 referenceNumber 51 publisherAbbreviation HighWire pubmedID 15294875 source Hum. Molec. Genet. 13: 2303-2311, 2004. authors Oliveira, C., Westra, J. L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S., Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., {and 16 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.30998 publisherName John Wiley & Sons, Inc. title Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. mimNumber 120436 referenceNumber 52 publisherAbbreviation Wiley pubmedID 16283678 source Am. J. Med. Genet. 139A: 96-105, 2005. authors Ostergaard, J. R., Sunde, L., Okkels, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1007/s00439-005-0107-8 publisherName Springer title Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. mimNumber 120436 referenceNumber 53 publisherAbbreviation Springer pubmedID 16341550 source Hum. Genet. 119: 9-22, 2006. authors Pagenstecher, C., Wehner, M., Friedl, W., Rahner, N., Aretz, S., Friedrichs, N., Sengteller, M., Henn, W., Buettner, R., Propping, P., Mangold, E. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8128251 publisherName HighWire Press title Mutation of a mutL homolog in hereditary colon cancer. mimNumber 120436 referenceNumber 54 publisherAbbreviation HighWire pubmedID 8128251 source Science 263: 1625-1629, 1994. authors Papadopoulos, N., Nicolaides, N. C., Wei, Y.-F., Ruben, S. M., Carter, K. C., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Hamilton, S. R., Petersen, G. M., Watson, P., Lynch, H. T., Peltomaki, P., Mecklin, J.-P., de la Chapelle, A., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://highwire.stanford.edu title Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome. mimNumber 120436 referenceNumber 55 pubmedID 7705822 source Hum. Path. 26: 422-427, 1995. authors Paraf, F., Sasseville, D., Watters, A. K., Narod, S., Ginsburg, O., Shibata, H., Jothy, S. pubmedImages false articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1098-3600&volume=13&issue=10&spage=895 publisherName Lippincott Williams & Wilkins title A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. mimNumber 120436 referenceNumber 56 publisherAbbreviation LWW pubmedID 21785361 source Genet. Med. 13: 895-902, 2011. authors Pinheiro, M., Pinto, C., Peixoto, A., Veiga, I., Mesquita, B., Henrique, R., Baptista, M., Fragoso, M., Sousa, O., Pereira, H., Marinho, C., Dias, L. M., Teixeira, M. R. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://dx.doi.org/10.1002/cncr.22697 publisherName John Wiley & Sons, Inc. title Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. mimNumber 120436 referenceNumber 57 publisherAbbreviation Wiley pubmedID 17440981 source Cancer 109: 2349-2356, 2007. authors Poley, J.-W., Wagner, A., Hoogmans, M. M. C. P., Menko, F. H., Tops, C., Kros, J. M., Reddingius, R. E., Meijers-Heijboer, H., Kuipers, E. J., Dinjens, W. N. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15937084 publisherName HighWire Press title Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. mimNumber 120436 referenceNumber 58 publisherAbbreviation HighWire pubmedID 15937084 source J. Med. Genet. 42: 491-496, 2005. authors Quehenberger, F., Vasen, H. F. A., van Houwelingen, H. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/gcc.20040 publisherName John Wiley & Sons, Inc. title HNPCC mutation MLHI P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type I. mimNumber 120436 referenceNumber 59 publisherAbbreviation Wiley pubmedID 15139004 source Genes Chromosomes Cancer 40: 261-265, 2004. authors Raevaara, T. E., Gerdes, A.-M., Lonnqvist, K. E., Tybjaerg-Hansen, A., Abdel-Rahman, W. M., Kariola, R., Peltomaki, P., Nystrom-Lahti, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0165-4608(04)00141-4 publisherName Elsevier Science title Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer. mimNumber 120436 referenceNumber 60 publisherAbbreviation ES pubmedID 15571801 source Cancer Genet. Cytogenet. 155: 149-151, 2004. authors Rey, J.-M., Noruzinia, M., Brouillet, J.-P., Sarda, P., Maudelonde, T., Pujol, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9927033 publisherName HighWire Press title Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. mimNumber 120436 referenceNumber 61 publisherAbbreviation HighWire pubmedID 9927033 source Cancer Res. 59: 290-293, 1999. authors Ricciardone, M. D., Ozcelik, T., Cevher, B., Ozdag, H., Tuncer, M., Gurgey, A., Uzunalimoglu, O., Cetinkaya, H., Tanyeli, A., Erken, E., Ozturk, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1996)7:3<275::AID-HUMU15>3.0.CO;2-%23 publisherName John Wiley & Sons, Inc. title Somatic mutations of a human mismatch repair gene, hMLH1, in tumors from patients with multiple primary cancers. mimNumber 120436 referenceNumber 62 publisherAbbreviation Wiley pubmedID 8829664 source Hum. Mutat. 7: 275-278, 1996. authors Sasaki, S., Horii, A., Shimada, M., Han, H.-J., Yanagisawa, A., Muto, T., Nakamura, Y. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/1277 publisherName Nature Publishing Group title Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. mimNumber 120436 referenceNumber 63 publisherAbbreviation NPG pubmedID 9697702 source Nature Genet. 19: 384-389, 1998. 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J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11585727 publisherName HighWire Press title A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families. mimNumber 120436 referenceNumber 65 publisherAbbreviation HighWire pubmedID 11585727 source Cancer Res. 61: 7020-7024, 2001. authors Stella, A., Wagner, A., Shito, K., Lipkin, S. M., Watson, P., Guanti, G., Lynch, H. T., Fodde, R., Liu, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1342 publisherName Nature Publishing Group title Germline epimutation of MLH1 in individuals with multiple cancers. mimNumber 120436 referenceNumber 66 publisherAbbreviation NPG pubmedID 15064764 source Nature Genet. 36: 497-501, 2004. Note: Erratum: Nature Genet. 39: 1414 only, 2007. authors Suter, C. M., Martin, D. I. K., Ward, R. 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Genet. 75: 334-345, 2009. authors Tang, R., Hsiung, C., Wang, J.-Y., Lai, C.-H., Chien, H.-T., Chiu, L.-L., Liu, C.-T., Chen, H.-H., Wang, H.-M., Chen, S.-X., Hsieh, L.-L., {the TCOG HNPCC Consortium} pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/humu.10291 publisherName John Wiley & Sons, Inc. title Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. mimNumber 120436 referenceNumber 68 publisherAbbreviation Wiley pubmedID 14635101 source Hum. Mutat. 22: 428-433, 2003. authors Taylor, C. F., Charlton, R. S., Burn, J., Sheridan, E., Taylor, G. R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.20796 publisherName John Wiley & Sons, Inc. title A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. mimNumber 120436 referenceNumber 69 publisherAbbreviation Wiley pubmedID 18561205 source Hum. Mutat. 29: 1412-1424, 2008. authors Tournier, I., Vezain, M., Martins, A., Charbonnier, F., Baert-Desurmont, S., Olschwang, S., Wang, Q., Buisine, M. P., Soret, J., Tazi, J., Frebourg, T., Tosi, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=1389-9600&volume=1&page=101 publisherName Springer title Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? mimNumber 120436 referenceNumber 70 publisherAbbreviation Springer pubmedID 14574005 source Fam. Cancer 1: 101-105, 2001. authors Trimbath, J. D., Petersen, G. M., Erdman, S. H., Ferre, M., Luce, M. C., Giardiello, F. M. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0016508502075790 publisherName Elsevier Science title Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. mimNumber 120436 referenceNumber 71 publisherAbbreviation ES pubmedID 11781295 source Gastroenterology 122: 211-219, 2002. authors Trojan, J., Zeuzem, S., Randolph, A., Hemmerle, C., Brieger, A., Raedle, J., Plotz, G., Jiricny, J., Marra, G. pubmedImages false publisherUrl http://www.elsevier.com/ title The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). mimNumber 120436 referenceNumber 72 pubmedID 2022152 source Dis. Colon Rectum 34: 424-425, 1991. authors Vasen, H. F., Mecklin, J. P., Khan, P. M., Lynch, H. T. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9671741 publisherName HighWire Press title Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. mimNumber 120436 referenceNumber 73 publisherAbbreviation HighWire pubmedID 9671741 source Proc. Nat. Acad. Sci. 95: 8698-8702, 1998. authors Veigl, M. L., Kasturi, L., Olechnowicz, J., Ma, A., Lutterbaugh, J. D., Periyasamy, S., Li, G.-M., Drummond, J., Modrich, P. L., Sedwick, W. D., Markowitz, S. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10138 publisherName John Wiley & Sons, Inc. title Different molecular mechanisms underlie genomic deletions in the MLH1 gene. mimNumber 120436 referenceNumber 74 publisherAbbreviation Wiley pubmedID 12402334 source Hum. Mutat. 20: 368-374, 2002. authors Viel, A., Petronzelli, F., Della Puppa, L., Lucci-Cordisco, E., Fornasarig, M., Pucciarelli, S., Rovella, V., Quaia, M., Ponz de Leon, M., Boiocchi, M., Genuardi, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11389087 publisherName HighWire Press title Extensive somatic microsatellite mutations in normal human tissue. mimNumber 120436 referenceNumber 75 publisherAbbreviation HighWire pubmedID 11389087 source Cancer Res. 61: 4541-4544, 2001. authors Vilkki, S., Tsao, J.-L., Loukola, A., Poyhonen, M., Vierimaa, O., Herva, R., Aaltonen, L. A., Shibata, D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9927034 publisherName HighWire Press title Neurofibromatosis and early onset of cancers in hMLH1-deficient children. mimNumber 120436 referenceNumber 76 publisherAbbreviation HighWire pubmedID 9927034 source Cancer Res. 59: 294-297, 1999. authors Wang, Q., Lasset, C., Desseigne, F., Frappaz, D., Bergeron, C., Navarro, C., Ruano, E., Puisieux, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1007/s00439-002-0858-4 publisherName Springer title Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. mimNumber 120436 referenceNumber 77 publisherAbbreviation Springer pubmedID 12522551 source Hum. Genet. 112: 117-123, 2003. authors Wang, Q., Montmain, G., Ruano, E., Upadhyaya, M., Dudley, S., Liskay, R. M., Thibodeau, S. N., Puisieux, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=10783165 publisherName HighWire Press title BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. mimNumber 120436 referenceNumber 78 publisherAbbreviation HighWire pubmedID 10783165 source Genes Dev. 14: 927-939, 2000. authors Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/7100003/71000362.htm publisherName Springer title Hereditary nonpolyposis colorectal cancer: causative role of a germline missense mutation in the hMLH1 gene confirmed by the independent occurrence of the same somatic mutation in tumour tissue. mimNumber 120436 referenceNumber 79 publisherAbbreviation Springer pubmedID 9272156 source Hum. Genet. 100: 362-364, 1997. authors Wang, Y., Friedl, W., Lamberti, C., Ruelfs, C., Kruse, R., Propping, P. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1038/gim.2012.91 publisherName Nature Publishing Group title Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. mimNumber 120436 referenceNumber 80 publisherAbbreviation NPG pubmedID 22878509 source Genet. Med. 15: 25-35, 2013. authors Ward, R. L., Dobbins, T., Lindor, N. M., Rapkins, R. W., Hitchins, M. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2003&volume=64&issue=3&spage=243 publisherName Blackwell Publishing title Low mutation rate of hMSH2 and hMLH1 in Taiwanese hereditary non-polyposis colorectal cancer. mimNumber 120436 referenceNumber 81 publisherAbbreviation Blackwell pubmedID 12919140 source Clin. Genet. 64: 243-251, 2003. authors Wei, S.-C., Yu, C.-Y., Tsai-Wu, J.-J., Su, Y.-N., Sheu, J.-C., Wu, C.-H. H., Wang, C.-Y., Wong, J.-M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10922385 publisherName HighWire Press title The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers. mimNumber 120436 referenceNumber 82 publisherAbbreviation HighWire pubmedID 10922385 source J. Med. Genet. 37: 588-592, 2000. authors Wheeler, J. M. D., Loukola, A., Aaltonen, L. A., McC Mortensen, N. J., Bodmer, W. F. pubmedImages false publisherUrl http://highwire.stanford.edu title Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. mimNumber 120436 referenceNumber 83 pubmedID 8571956 source Am. J. Hum. Genet. 58: 300-307, 1996. authors Wijnen, J., Khan, P. M., Vasen, H., Menko, F., van der Klift, H., van den Broek, M., van Leeuwen-Cornelisse, I., Nagengast, F., Meijers-Heijboer, E. J., Lindhout, D., Griffioen, G., Cats, A., Kleibeuker, J., Varesco, L., Bertario, L., Bisgaard, M.-L., Mohr, J., Kolodner, R., Fodde, R. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1998&volume=54&issue=4&spage=368 publisherName Blackwell Publishing title I1307K APC and hMLH1 mutations in a non-Jewish family with hereditary non-polyposis colorectal cancer. mimNumber 120436 referenceNumber 84 publisherAbbreviation Blackwell pubmedID 9831355 source Clin. Genet. 54: 368-370, 1998. authors Yuan, Z. Q., Kasprzak, L., Gordon, P. H., Pinsky, L., Foulkes, W. D. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ externalLinks cmgGene false mgiHumanDisease false hprdIDs 00390 nbkIDs NBK1211;;Lynch Syndrome refSeqAccessionIDs NG_007109.2 uniGenes Hs.195364 approvedGeneSymbols MLH1 nextGxDx true locusSpecificDBs http://www.insight-group.org/;;Hereditary Non-Polyposis Colorectal Cancer, HNPCC;;;http://www.med.mun.ca/mmrvariants/;;Mismatch Repair Genes Variant Database;;;http://databases.lovd.nl/genomed/home.php?select_db=MLH1;;Zhejiang University-Adinovo Center MLH1 Database flybaseIDs FBgn0011659 dermAtlas false umlsIDs C0879389 gtr true geneIDs 4292 swissProtIDs P40692 zfinIDs ZDB-GENE-040426-1600 ensemblIDs ENSG00000076242,ENST00000231790 geneTests true mgiIDs MGI:101938 ncbiReferenceSequences 530372509,530372511,263191588,384871675,263191712,384871680,384871682,263191547,530372517,530372519,263191732,530372513,530372515 genbankNucleotideSequences 34368009,221044259,164696129,71518807,194390915,466461,194391309,2160768,211637566,62897178,157928133,13905125,221045535,604349,604351,604350,221045915,164690408,194379945,604361,604360,158514355,604363,604362,158514353,604365,604364,158514359,604367,48476965,604366,158514357,604353,24431549,604352,604355,27805154,604354,164696090,604357,604356,604359,604358,158514339,998493,148167303,33622354,158514337,158514343,158514341,158514347,158514345,148167304,148167305,158514351,80934669,158514349,110164976,110164978,11693399,47402549,511856617,511856622,511856620,52001527,157928838,62089281,463988,10988112,110164968,1079785,110164970,110164972,110164974 proteinSequences 530372510,221044260,263191589,221045536,384871676,263191713,194390916,194391310,466462,263191733,2160769,211637567,189069159,62897179,730028,157928134,221045916,13905126,530372520,530372516,194379946,530372514,158514354,158514352,158514358,48476966,158514356,158514360,27805155,158514338,998494,33622355,158514342,158514340,119584887,604369,119584888,158514346,119584889,158514344,158514350,158514348,52001528,110164977,110164979,157928839,62089282,384871681,463989,384871683,4557757,110164969,1079787,110164971,110164973,110164975 geneticsHomeReferenceIDs gene;;MLH1;;MLH1

entryList

entry status live allelicVariantExists true epochCreated 1011772800 geneMap geneSymbols GNMT sequenceID 4995 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 606628 phenotypeInheritance Autosomal recessive phenotype Glycine N-methyltransferase deficiency phenotypeMimNumber 606664 chromosomeLocationStart 42928499 chromosomeSort 446 chromosomeSymbol 6 mimNumber 606628 geneInheritance None confidence P mappingMethod A geneName Glycine N-methyltransferase mouseMgiID MGI:1202304 mouseGeneSymbol Gnmt computedCytoLocation 6p21.1 cytoLocation 6p12 transcript uc003otd.3 chromosomeLocationEnd 42931617 chromosome 6 contributors Ada Hamosh - updated : 3/9/2009 Victor A. McKusick - updated : 1/25/2002 externalLinks flybaseIDs FBgn0038074 mgiIDs MGI:1202304 mgiHumanDisease false nextGxDx false ncbiReferenceSequences 54792737 refSeqAccessionIDs NG_008396.1 dermAtlas false hprdIDs 05970 swissProtIDs Q14749 zfinIDs ZDB-GENE-040227-1 uniGenes Hs.144914 gtr true cmgGene false ensemblIDs ENSG00000124713,ENST00000372808 umlsIDs C1415165 genbankNucleotideSequences 123994596,148141461,209402777,71516736,123979831,433939,511815095,511815096,8671581,8671583,21619157,11610974 geneTests true approvedGeneSymbols GNMT geneIDs 27232 proteinSequences 119624529,12644416,119624528,123994597,209402778,8671584,9506741,1335203,8671582,123979832,21619158 geneticsHomeReferenceIDs gene;;GNMT;;GNMT clinicalSynopsisExists false mimNumber 606628 allelicVariantList allelicVariant status live name GLYCINE N-METHYLTRANSFERASE DEFICIENCY dbSnps rs121907888 text In 2 Italian sibs with GNMT deficiency ({606664}) reported by {5:Mudd et al. (2001)}, {4:Luka et al. (2002)} found compound heterozygosity for 2 missense mutations in the GNMT gene. One mutation was a 1481T-C transition in exon 1 resulting in a leu49-to-pro substitution; the other was a 3715C-A transversion in exon 4 resulting in a his176-to-asn substitution ({606628.0002}). The mother was heterozygous for the former mutation, and the father was heterozygous for latter. mutations GNMT, LEU49PRO number 1 clinvarAccessions RCV000004386;;1 status live name GLYCINE N-METHYLTRANSFERASE DEFICIENCY dbSnps rs121907889 text See {606628.0001} and {4:Luka et al. (2002)}. mutations GNMT, HIS176ASN number 2 clinvarAccessions RCV000004387;;1 prefix * titles preferredTitle GLYCINE N-METHYLTRANSFERASE; GNMT textSectionList textSection textSectionTitle Description textSectionContent Glycine N-methyltransferase (GNMT; {EC 2.1.1.20}) catalyzes the synthesis of N-methylglycine (sarcosine) from glycine using S-adenosylmethionine (AdoMet) as the methyl donor. The enzyme was first described by {1:Blumenstein and Williams (1960)} in guinea pig liver. GNMT acts as an enzyme to regulate the ratio of S-adenosylmethionine to S-adenosylhomocysteine (AdoHcy) and participates in the detoxification pathway in liver cells. textSectionName description textSectionTitle Cloning textSectionContent {3:Chen et al. (1998)} isolated a full-length GNMT cDNA, consisting of 1,096 nucleotides, from a liver cDNA library. This clone differed in 4 nucleotides from one isolated by {7:Ogawa et al. (1993)}, with a resulting change in 1 amino acid (residue 24 changed from glutamic acid to aspartic acid). {2:Chen et al. (2000)} isolated a human GNMT gene by screening a human placenta genomic library with the cDNA isolated by {3:Chen et al. (1998)}. Northern blot analysis detected expression of the 1.8-kb GNMT mRNA only in adult liver, pancreas, and prostate, and fetal liver. textSectionName cloning textSectionTitle Gene Structure textSectionContent The human GNMT gene comprises 6 exons and spans 10 kb ({2:Chen et al., 2000}). textSectionName geneStructure textSectionTitle Gene Function textSectionContent Using a combination of high-throughput liquid and gas chromatography-based mass spectrometry, {8:Sreekumar et al. (2009)} profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer, and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that is highly increased during prostate cancer progression to metastasis and can be detected noninvasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase ({604455}), induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor (AR; {313700}) and the ERG gene fusion product (see {165080}) coordinately regulate components of the sarcosine pathway. {8:Sreekumar et al. (2009)} concluded that by profiling the metabolomic alterations of prostate cancer progression, they revealed sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. textSectionName geneFunction textSectionTitle Mapping textSectionContent {2:Chen et al. (2000)} mapped the GNMT gene to chromosome 6p12 by FISH. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent In 2 Italian sibs with GNMT deficiency ({606664}) reported by {5:Mudd et al. (2001)}, {4:Luka et al. (2002)} found compound heterozygosity for 2 missense mutations of the GNMT gene: leu49 to pro ({606628.0001}) and his176 to asn ({606628.0002}). These were the first reported cases of an inborn error affecting the activity of GNMT. textSectionName molecularGenetics geneMapExists true editHistory alopez : 10/01/2013 alopez : 3/10/2009 terry : 3/9/2009 carol : 1/31/2002 terry : 1/25/2002 alopez : 1/23/2002 dateCreated Wed, 23 Jan 2002 03:00:00 EST creationDate Ada Hamosh : 1/23/2002 epochUpdated 1380610800 dateUpdated Tue, 01 Oct 2013 03:00:00 EDT referenceList reference source Biochem. Biophys. Res. Commun. 3: 259-263, 1960. mimNumber 606628 authors Blumenstein, J., Williams, G. R. title The enzymic N-methylation of glycine. referenceNumber 1 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(00)96188-3 publisherName Elsevier Science title Genomic structure, expression, and chromosomal localization of the human glycine N-methyltransferase gene. mimNumber 606628 referenceNumber 2 publisherAbbreviation ES pubmedID 10843803 source Genomics 66: 43-47, 2000. authors Chen, Y.-M. A., Chen, L.-Y., Wong, F.-H., Lee, C.-M., Chang, T.-J., Yang-Feng, T. L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1097-0215(19980302)75:5<787::AID-IJC20>3.0.CO;2-2 publisherName John Wiley & Sons, Inc. title Characterization of glycine-N-methyltransferase-gene expression in human hepatocellular carcinoma. mimNumber 606628 referenceNumber 3 publisherAbbreviation Wiley pubmedID 9495250 source Int. J. Cancer 75: 787-793, 1998. authors Chen, Y.-M. A., Shiu, J.-Y. A., Tzeng, S. J., Shih, L.-S., Chen, Y.-J., Lui, W.-Y., Chen, P.-H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1007/s00439-001-0648-4 publisherName Springer title Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. mimNumber 606628 referenceNumber 4 publisherAbbreviation Springer pubmedID 11810299 source Hum. Genet. 110: 68-74, 2002. authors Luka, Z., Cerone, R., Phillips, J. A., III, Mudd, S. H., Wagner, C. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=24&page=448 publisherName Springer title Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. mimNumber 606628 referenceNumber 5 publisherAbbreviation Springer pubmedID 11596649 source J. Inherit. Metab. Dis. 24: 448-464, 2001. authors Mudd, S. H., Cerone, R., Schiaffino, M. C., Fantasia, A. R., Minniti, G., Caruso, U., Lorini, R., Watkins, D., Matiaszuk, N., Rosenblatt, D. S., Schwahn, B., Rozen, R., LeGros, L., Kotb, M., Capdevila, A., Luka, Z., Finkelstein, J. D., Tangerman, A., Stabler, S. P., Allen, R. H., Wagner, C. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0026-0495(80)90192-4 publisherName Elsevier Science title Labile methyl group balances in the human: the role of sarcosine. mimNumber 606628 referenceNumber 6 publisherAbbreviation ES pubmedID 6157075 source Metabolism 29: 707-720, 1980. authors Mudd, S. H., Ebert, M. H., Scriver, C. R. pubmedImages false publisherUrl http://www.elsevier.com/ source Comp. Biochem. Physiol. 106B: 601-611, 1993. mimNumber 606628 authors Ogawa, H., Gomi, T., Fujioka, M. title Mammalian glycine N-methyltransferases. Comparative kinetic and structural properties of the enzymes from human, rat, rabbit and pig livers. referenceNumber 7 articleUrl http://dx.doi.org/10.1038/nature07762 publisherName Nature Publishing Group title Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. mimNumber 606628 referenceNumber 8 publisherAbbreviation NPG pubmedID 19212411 source Nature 457: 910-914, 2009. Note: Erratum: Nature 499: 504 only, 2013. authors Sreekumar, A., Poisson, L. M., Rajendiran, T. M., Khan, A. P., Cao, Q., Yu, J., Laxman, B., Mehra, R., Lonigro, R. J., Li, Y., Nyati, M. K., Ahsan, A., {and 14 others} pubmedImages true publisherUrl http://www.nature.com seeAlso Mudd et al. (1980)

entryList

entry status live allelicVariantExists true epochCreated 652690800 geneMap geneSymbols NPR2, ANPRB, AMDM, ECDM sequenceID 6853 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 108961 phenotypeInheritance Autosomal recessive phenotype Acromesomelic dysplasia, Maroteaux type phenotypeMimNumber 602875 phenotypeMappingKey 3 mimNumber 108961 phenotypeInheritance Autosomal dominant phenotype Epiphyseal chondrodysplasia, Miura type phenotypeMimNumber 615923 chromosomeLocationStart 35789961 chromosomeSort 156 chromosomeSymbol 9 mimNumber 108961 geneInheritance None confidence P mappingMethod REa, A, Fd geneName Natiuretic peptide receptor 2 mouseMgiID MGI:97372 mouseGeneSymbol Npr2 computedCytoLocation 9p13.3 cytoLocation 9p21-p12 transcript uc003zyd.3 chromosomeLocationEnd 35809727 chromosome 9 contributors Ingrid M. Wentzensen - updated : 8/5/2014 Patricia A. Hartz - updated : 5/23/2014 Ada Hamosh - updated : 11/29/2010 Ada Hamosh - updated : 5/14/2009 George E. Tiller - updated : 4/15/2009 John A. Phillips, III - updated : 4/18/2007 Patricia A. Hartz - updated : 2/17/2005 Victor A. McKusick - updated : 6/10/2004 clinicalSynopsisExists false mimNumber 108961 allelicVariantList allelicVariant status live name ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE dbSnps rs28931581 text In a consanguineous Brazilian family with acromesomelic dysplasia, type Maroteaux ({602875}), {1:Bartels et al. (2004)} described a 94C-A transversion in the NPR2 cDNA, resulting in a pro32-to-thr (P32T) change in the protein, as the molecular basis of the disorder. mutations NPR2, PRO32THR number 1 clinvarAccessions RCV000019362;;1 status live name ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE dbSnps rs28931582 text In a consanguineous Turkish family with acromesomelic dysplasia, type Maroteaux ({602875}), {1:Bartels et al. (2004)} found a 343T-G transversion in the NPR2 cDNA, causing a trp115-to-gly amino acid substitution (W115G), as the basis of the disorder. mutations NPR2, TRP115GLY number 2 clinvarAccessions RCV000019363;;1 status live name ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE dbSnps rs28929479 text In a nonconsanguineous U.S. white family with acromesomelic dysplasia, type Maroteaux ({602875}), {1:Bartels et al. (2004)} found compound heterozygosity for a missense mutation and a premature stop mutation in the NPR2 gene as the basis of the disorder. The allele inherited from the mother carried a 528T-A transversion, resulting in an asp176-to-glu (D176E) change in the protein. The father's allele carried a 1162C-T transition resulting in an arg388-to-ter (R388X) mutation ({108961.0004}). The father was 170 cm tall as compared to the average matched control height of 177 cm; the mother was 150 cm tall as compared with the average matched control of 163.3 cm. mutations NPR2, ASP176GLU number 3 clinvarAccessions RCV000019364;;1 status live name ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE dbSnps rs121912739 text See {108961.0003} and {1:Bartels et al. (2004)}. mutations NPR2, ARG388TER number 4 clinvarAccessions RCV000019365;;1 status live name EPIPHYSEAL CHONDRODYSPLASIA, MIURA TYPE dbSnps rs587777595 text In all 3 affected members of a Japanese family segregating Miura-type epiphyseal chondrodysplasia (ECDM; {615923}), {10:Miura et al. (2012)} identified a heterozygous c.2647G-A transition in the NPR2 gene, resulting in a val833-to-met (V833M) substitution at a highly conserved residue in the C-terminal guanylyl cyclase domain, which was predicted to cause a gain of function. The mutation was not present in the dbSNP of JSNP databases or in 214 alleles from Japanese controls. Transfection experiments showed a gain of function of this variant with increased cGMP production, independent of C-type natriuretic peptide in HEK293A transfected cells. {13:Robinson et al. (2013)} performed transfection experiments with the NPR2 V833M mutation in HEK293 cells and showed that the variant led to a 20-fold increase in cGMP levels by activating guanylyl cyclase B in the absence of CNP. Enzyme analysis showed that basal activity of V883M guanylyl cyclase B was elevated, with reduced expression levels. Substrate velocity experiments indicated that the V883M mutation increases basal maximal velocity and allows CNP to reduce the Michaelis constant (Km) in the absence of ATP. The authors concluded that this mutation might lead to a structural change that locks the enzyme in a conformation mimicking the ATP-bound state. mutations NPR2, VAL833MET number 5 clinvarAccessions RCV000132560;;1 status live name EPIPHYSEAL CHONDRODYSPLASIA, MIURA TYPE dbSnps rs587777596 text By exome sequencing in a patient with extremely tall stature (+5 SD) and mild skeletal deformities (ECDM; {615923}), {5:Hannema et al. (2013)} identified a heterozygous c.1963C-T transition in the NPR2 gene, resulting in an arg655-to-cys (R655C) substitution in the kinase homology domain (KHD). The mutation, which was predicted to result in a gain of function, was not found in the patient's son or sister. Ex vivo studies of the proband's fibroblasts confirmed that the exogeneously expressed variant mediated markedly enhanced CNP/cGMP signaling. mutations NPR2, ARG655CYS number 6 clinvarAccessions RCV000132561;;1 status live name EPIPHYSEAL CHONDRODYSPLASIA, MIURA TYPE dbSnps rs587777597 text In affected members of a Korean kindred with Miura-type epiphyseal chondrodysplasia (ECDM; {615923}), {9:Miura et al. (2014)} identified a heterozygous c.1462G-C transversion in the NPR2 gene, resulting in an ala488-to-pro (A488P) substitution at a highly conserved residue in the juxtamembranous cytoplasmic domain. This sequence variation eliminates a NheI cleavage site. The mutation, which was confirmed by Sanger sequencing, was not present in unaffected family members, in the dbSNP (build 137) or NHLBI Exome Sequencing Project databases, or in 400 alleles of Korean or Japanese controls. The mutation was predicted to lead to a gain of function. Transfection experiments with HEK293A cells showed equal expression of both wildtype and mutated allele, but only the latter showed production of cGMP in the absence of CNP. mutations NPR2, ALA488PRO number 7 clinvarAccessions RCV000132562;;1 prefix * titles alternativeTitles GUANYLATE CYCLASE B; GCB;; GUC2B; GUCY2B;; ATRIAL NATRIURETIC PEPTIDE RECEPTOR, TYPE B; ANPRB;; ATRIONATRIURETIC PEPTIDE RECEPTOR, TYPE B; NPRB;; ANPB RECEPTOR preferredTitle NATRIURETIC PEPTIDE RECEPTOR 2; NPR2 textSectionList textSection textSectionTitle Description textSectionContent The NPR2 gene encodes a guanylate cyclase that catalyzes the converson of intracellular guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) (summary by {9:Miura et al., 2014}). textSectionName description textSectionTitle Cloning textSectionContent In the course of cloning the human ANPA receptor (NPR1; {108960}) from a placenta cDNA library, {2:Chang et al. (1989)} obtained an NPR2 clone, which they called ANPB receptor. The deduced 1,048-amino acid protein has a 22-amino acid signal peptide, followed by a 442-amino acid extracellular domain, which contains 7 potential N-glycosylation sites and 6 cysteines, a transmembrane domain, an arg-lys stop transfer sequence, and a 569-amino acid cytoplasmic domain, which contains 1 potential N-glycosylation site and 9 cysteines. The mature protein has a calculated molecular mass of approximately 115 kD. The cytoplasmic domain contains both a protein kinase domain and a guanylate cyclase domain. The ANPB receptor shares domain structure and significant amino acid identity with human ANPA receptor and bovine ANPC receptor (NPR3; {108962}). textSectionName cloning textSectionTitle Gene Function textSectionContent By assaying the membrane fraction of transfected COS-7 cells, {2:Chang et al. (1989)} found that expression of the human ANPB receptor increased membrane binding of radiolabeled human alpha-ANP (NPPA; {108780}) and bovine brain ANP (NPPB; {600295}) and increased production of cyclic GMP compared with controls. The homodimeric transmembrane receptor natriuretic peptide receptor B produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP, NPPC; {600296}) ({7:Lincoln and Cornwell., 1993}). {14:Sessions et al. (2009)} identified insect host factors required for dengue virus (see {614371}) propagation by carrying out a genomewide RNA interference screen in D. melanogaster cells using a well established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses, most of the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologs and, using a targeted short interfering RNA screen, they showed that 42 of these are human DVHFs. These include NPR2, SEC61B ({609214}), TMEM214, TAZ ({300394}), EXDL2, and CNOT2 ({604909}). {14:Sessions et al. (2009)} concluded that this overlap indicates notable conservation of required factors between dipteran and human hosts. {17:Zhang et al. (2010)} showed that mural granulosa cells, which line the follicle wall, express natriuretic peptide precursor type C (Nppc) mRNA, whereas cumulus cells surrounding oocytes express mRNA of the Nppc receptor Npr2, a guanylyl cyclase. Nppc increased cGMP levels in cumulus cells and oocytes and inhibited meiotic resumption in vitro. Meiotic arrest was not sustained in most Graafian follicles of Nppc or Npr2 mutant mice, and meiosis resumed precociously. Oocyte-derived paracrine factors promoted cumulus cell expression of Npr2 mRNA. Therefore, {17:Zhang et al. (2010)} concluded that the granulosa cell ligand NPPC and its receptor NPR2 in cumulus cells prevent precocious meiotic maturation and are therefore critical for maturation and ovulation synchrony and for normal female fertility. textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {12:Rehemudula et al. (1999)} determined that the NPR2 gene contains 22 coding exons and spans approximately 16.5 kb. The 5-prime flanking region contains 10 potential SP1 ({189906})-binding sites, but no TATA box. Intron 2 contains a CA/GT microsatellite repeat. textSectionName geneStructure textSectionTitle Mapping textSectionContent By PCR analysis of genomic DNA from somatic cell hybrids, {8:Lowe et al. (1990)} assigned the ANPRB gene to 9p22-p11. The localization was further narrowed to 9p21-p12 by in situ hybridization. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent Acromesomelic Dysplasia, Maroteaux Type Using a positional candidate approach, {1:Bartels et al. (2004)} identified mutations in the NPR2 gene as the cause of acromesomelic dysplasia, type Maroteaux (AMDM; {602875}), an autosomal recessive skeletal dysplasia. {1:Bartels et al. (2004)} sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice site mutations, and 11 missense mutations in the NPR2 gene. They found that obligate carriers of NPR2 mutations had heights below the mean for matched controls. In a functional assay of 3 missense mutations, they found markedly deficient guanylyl cyclase activity. CNP, the extracellular ligand of NPR2, is implicated in the regulation of skeletal growth in transgenic and knockout mice ({3:Chusho et al., 2001}; {16:Yasoda et al., 2004}). Since CNP is able to increase chondrocyte proliferation, matrix synthesis, and cell hypertrophy in the growth plate, {1:Bartels et al. (2004)} hypothesized that each of these effects is mediated by signaling via NPR2. {6:Hume et al. (2009)} hypothesized that missense mutations of NPRB associated with AMDM primarily affect NPRB function by the arrest of receptor trafficking at the endoplasmic reticulum (ER) due to conformational change, rather than an impairment of ligand binding, transmission of signal through the membrane, or catalytic activity. Twelve missense mutations found in AMDM patients and cn/cn mice were generated by site-directed mutagenesis and transiently overexpressed in HeLa cells. Confocal microscopy revealed that 11 of the 12 mutants were retained in the ER. Determination of the ligand-dependent cGMP response confirmed that ER-retained NPRB mutants were nonfunctional. Meanwhile, the only cell surface-targeted NPRB missense mutant (D176E; {108961.0003}) displayed greatly reduced enzymatic activity due to impaired ligand binding. The authors concluded that in the majority of cases of AMDM associated with missense NPRB mutations, disease appears to result from defects in the targeting of the ER receptor to the plasma membrane. Epiphyseal Chondrodysplasia, Miura Type In 3 Japanese family members with tall stature, macrodactyly of the great toes, and scoliosis (ECDM; {615923}), {10:Miura et al. (2012)} identified a heterozygous missense mutation in the NPR2 gene (V883M; {108961.0005}). Amino acid val883 is located in a highly conserved region of the carboxyl-terminal guanylyl cyclase domain of NPR2. Transfection experiments showed a gain of function of this variant with increased cGMP production, independent of C-type natriuretic peptide in HEK293A transfected cells. In a patient with tall stature (+5 SD), long fingers, mild scoliosis, and broad but not particularly long halluces, {5:Hannema et al. (2013)} identified a heterozygous mutation in the NPR2 gene (R655C; {108961.0006}). Ex vivo studies using fibroblasts of this patient as well as transfected HEK293A cells expressing mutant NPR2 showed markedly increased cGMP production, stimulated by C-type natriuretic peptide. Coimmunoprecipitation of FLAG-tagged wildtype NPR2 and Myc-tagged mutant NPR2 confirmed a tight interaction, suggesting an activating effect. In affected members of a 4-generation Korean kindred with tall stature, macrodactyly of the great toes, scoliosis, and coxa valga with epiphyseal dysplasia, {9:Miura et al. (2014)} identified a heterozygous missense mutation in the NPR2 gene (A488P; {108961.0007}). Serum NT-proCNP was not overproduced in the proband. An in vitro functional assay indicated that A488P is a gain-of-function mutation. Transfection experiments with HEK293A cells showed equal expression of both wildtype and mutated allele, but only the latter showed production of cGMP in the absence of CNP. Short Stature {11:Olney et al. (2006)} determined the phenotypic features of heterozygous carriers of NPR2 mutations in members of a single large kindred in which the proband had Maroteaux-type acromelic dysplasia. Sixteen family members were NPR2 mutation carriers. Height z-scores of these carriers were -1.8 +/- 1.1 (mean +/- standard deviation), which was significantly less than the 23 noncarrier family members and the general population. However, there was no difference in body proportion between carriers and noncarriers. The authors concluded that heterozygous mutations in NPR2 are associated with short stature. Assuming 1 in 700 persons unknowingly carries an NPR2 mutation, their data suggested that approximately 1 in 30 individuals with idiopathic short stature is a carrier of NPR2 mutations. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent By gene targeting, {15:Tamura et al. (2004)} generated mice lacking Npr2. Homozygous mutant pups were born at the expected mendelian ratios. Mutant animals exhibited self-clasping and priapism, suggesting neuronal disorders, but no histologic abnormalities were found in the brain and spinal cord of homozygous mutant mice. Npr2 null mice showed an impairment of endochondral ossification and attenuation of longitudinal vertebra or limb-bone growth, resulting in dwarfism that became more prominent as null mice grew older. Male Npr2 null mice were fertile, but female mutants were not, due to failure of the female reproductive tract to develop. {15:Tamura et al. (2004)} concluded that NPR2 is critical for the development of both bone and female reproductive organs. {4:Geister et al. (2013)} discovered a spontaneous mutant allele of mouse Npr2 named peewee (pwe) that caused severe disproportionate dwarfism and female infertility. They identified the pwe mutation as a 4-bp deletion in exon 3 of Npr2 that resulted in a frameshift and generation of a premature stop codon within the extracellular ligand-binding domain. Pwe homozygotes exhibited growth delay and disproportionate dwarfism that was evident at 2 weeks of age. The proximal skeletal elements of the appendicular skeleton were the most severely affected in pwe mouse. There was no reduction in the width of the skull or ribs, and the femur did not have a thinner dimension. Growth insufficiency of pwe mutants was indistinguishable from that of Npr2 -/- mice and was caused by reduction in the hypertrophic and proliferative zones of the growth plate. Mineralization of skeletal elements was normal. Female infertility was due to premature oocyte meiotic resumption, and the pituitary and uterus appeared to be normal. Treatment of fetal tibia explants with MAPK (see MAPK1; {176948}) inhibitors rescued the pwe growth defect. textSectionName animalModel geneMapExists true editHistory carol : 08/06/2014 carol : 8/5/2014 mgross : 5/23/2014 mcolton : 5/23/2014 carol : 4/12/2012 mgross : 12/1/2011 alopez : 12/1/2010 terry : 11/29/2010 alopez : 5/14/2009 alopez : 5/14/2009 alopez : 4/15/2009 alopez : 4/18/2007 mgross : 2/17/2005 terry : 11/4/2004 alopez : 6/11/2004 terry : 6/10/2004 mark : 12/29/1996 terry : 5/17/1996 carol : 4/19/1994 supermim : 3/16/1992 carol : 11/7/1990 carol : 10/9/1990 supermim : 9/28/1990 carol : 9/7/1990 dateCreated Fri, 07 Sep 1990 03:00:00 EDT creationDate Victor A. McKusick : 9/7/1990 epochUpdated 1407308400 dateUpdated Wed, 06 Aug 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61990-9 publisherName Elsevier Science title Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. mimNumber 108961 referenceNumber 1 publisherAbbreviation ES pubmedID 15146390 source Am. J. Hum. Genet. 75: 27-34, 2004. authors Bartels, C. F., Bukulmez, H., Padayatti, P., Rhee, D. K., van Ravenswaaij-Arts, C., Pauli, R. M., Mundlos, S., Chitayat, D., Shih, L.-Y., Al-Gazali, L. I., Kant, S., Cole, T., {and 13 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/341068a0 publisherName Nature Publishing Group title Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. mimNumber 108961 referenceNumber 2 publisherAbbreviation NPG pubmedID 2570358 source Nature 341: 68-72, 1989. authors Chang, M., Lowe, D. G., Lewis, M., Hellmiss, R., Chen, E., Goeddel, D. V. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11259675 publisherName HighWire Press title Dwarfism and early death in mice lacking C-type natriuretic peptide. mimNumber 108961 referenceNumber 3 publisherAbbreviation HighWire pubmedID 11259675 source Proc. Nat. Acad. Sci. 98: 4016-4021, 2001. authors Chusho, H., Tamura, N., Ogawa, Y., Yasoda, A., Suda, M., Miyazawa, T., Nakamura, K., Nakao, K., Kurihara, T., Komatsu, Y., Itoh, H., Tanaka, K., Saito, Y., Katsuki, M., Nakao, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=23065701 publisherName HighWire Press title A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type. mimNumber 108961 referenceNumber 4 publisherAbbreviation HighWire pubmedID 23065701 source Hum. Molec. Genet. 22: 345-357, 2013. authors Geister, K. A., Brinkmeier, M. L., Hsieh, M., Faust, S. M., Karolyi, I. J., Perosky, J. E., Kozloff, K. M., Conti, M., Camper, S. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://press.endocrine.org/doi/abs/10.1210/jc.2013-2358?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. mimNumber 108961 referenceNumber 5 publisherAbbreviation ATYPON pubmedID 24057292 source J. Clin. Endocr. Metab. 98: E1988-E1998, 2013. Note: Electronic Article. authors Hannema, S. E., van Duyvenvoorde, H. A., Premsler, T., Yang, R.-B., Mueller, T. D., Gassner, B., Oberwinkler, H., Roelfsema, F., Santen, G. W. E., Prickett, T., Kant, S. G., Verkerk, A. J. M. H., Uitterlinden, A. G., Espiner, E., Ruivenkamp, C. A. L., Oostdijk, W., Pereira, A. M., Losekoot, M., Kuhn, M., Wit, J. M. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18945719 publisherName HighWire Press title Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux. mimNumber 108961 referenceNumber 6 publisherAbbreviation HighWire pubmedID 18945719 source Hum. Molec. Genet. 18: 267-277, 2009. authors Hume, A. N., Buttgereit, J., Al-Awadhi, A. M., Al-Suwaidi, S. S., John, A., Bader, M., Seabra, M. C., Al-Gazali, L., Ali, B. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=7680013 publisherName HighWire Press title Intracellular cyclic GMP receptor proteins. mimNumber 108961 referenceNumber 7 publisherAbbreviation HighWire pubmedID 7680013 source FASEB J. 7: 328-338, 1993. authors Lincoln, T. M., Cornwell, T. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0888-7543(90)90286-4 publisherName Elsevier Science title Chromosomal distribution of three members of the human natriuretic peptide receptor/guanylyl cyclase gene family. mimNumber 108961 referenceNumber 8 publisherAbbreviation ES pubmedID 1979052 source Genomics 8: 304-312, 1990. authors Lowe, D. G., Klisak, I., Sparkes, R. S., Mohandas, T., Goeddel, D. V. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.36218 publisherName John Wiley & Sons, Inc. title Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. mimNumber 108961 referenceNumber 9 publisherAbbreviation Wiley pubmedID 24259409 source Am. J. Med. Genet. 164A: 156-163, 2014. authors Miura, K., Kim, O.-H., Lee, H. R., Namba, N., Michigami, T., Yoo, W. J., Choi, I. H., Ozono, K., Cho, T.-J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.plos.org/10.1371/journal.pone.0042180 publisherName Public Library of Science title An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. mimNumber 108961 referenceNumber 10 publisherAbbreviation PLoS pubmedID 22870295 source PLoS One 7: e42180, 2012. Note: Electronic Article. authors Miura, K., Namba, N., Fujiwara, M., Ohata, Y., Ishida, H., Kitaoka, T., Kubota, T., Hirai, H., Higuchi, C., Tsumaki, N., Yoshikawa, H., Sakai, N., Michigami, T., Ozono, K. pubmedImages false publisherUrl http://www.plos.org/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=16384845 publisherName HighWire Press title Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. mimNumber 108961 referenceNumber 11 publisherAbbreviation HighWire pubmedID 16384845 source J. Clin. Endocr. Metab. 91: 1229-1232, 2006. authors Olney, R. C., Bukulmez, H., Bartels, C. F., Prickett, T. C. R., Espiner, E. A., Potter, L. R., Warman, M. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=10082481 publisherName HighWire Press title Structure of the type B human natriuretic peptide receptor gene and association of a novel microsatellite polymorphism with essential hypertension. mimNumber 108961 referenceNumber 12 publisherAbbreviation HighWire pubmedID 10082481 source Circ. Res. 84: 605-610, 1999. authors Rehemudula, D., Nakayama, T., Soma, M., Takahashi, Y., Uwabo, J., Sato, M., Izumi, Y., Kanmatsuse, K., Ozawa, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S8756-3282(13)00242-1 publisherName Elsevier Science title A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B. mimNumber 108961 referenceNumber 13 publisherAbbreviation ES pubmedID 23827346 source Bone 56: 375-382, 2013. authors Robinson, J. W., Dickey, D. M., Miura, K., Michigami, T., Ozono, K., Potter, L. R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nature07967 publisherName Nature Publishing Group title Discovery of insect and human dengue virus host factors. mimNumber 108961 referenceNumber 14 publisherAbbreviation NPG pubmedID 19396146 source Nature 458: 1047-1050, 2009. authors Sessions, O. M., Barrows, N. J., Souza-Neto, J. A., Robinson, T. J., Hershey, C. L., Rodgers, M. A., Ramirez, J. L., Dimopoulos, G., Yang, P. L., Pearson, J. L., Garcia-Blanco, M. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15572448 publisherName HighWire Press title Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. mimNumber 108961 referenceNumber 15 publisherAbbreviation HighWire pubmedID 15572448 source Proc. Nat. Acad. Sci. 101: 17300-17305, 2004. authors Tamura, N., Doolittle, L. K., Hammer, R. E., Shelton, J. M., Richardson, J. A., Garbers, D. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nm971 publisherName Nature Publishing Group title Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. mimNumber 108961 referenceNumber 16 publisherAbbreviation NPG pubmedID 14702637 source Nature Med. 10: 80-86, 2004. authors Yasoda, A., Komatsu, Y., Chusho, H., Miyazawa, T., Ozasa, A., Miura, M., Kurihara, T., Rogi, T., Tanaka, S., Suda, M., Tamura, N., Ogawa, Y., Nakao, K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=20947764 publisherName HighWire Press title Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. mimNumber 108961 referenceNumber 17 publisherAbbreviation HighWire pubmedID 20947764 source Science 330: 366-369, 2010. authors Zhang, M., Su, Y.-Q., Sugiura, K., Xia, G., Eppig, J. J. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks flybaseIDs FBgn0051183 mgiIDs MGI:97372 mgiHumanDisease false ncbiReferenceSequences 530389936,73915098,530389938 refSeqAccessionIDs NG_009249.1 dermAtlas false hprdIDs 00166 swissProtIDs P20594 zfinIDs ZDB-GENE-141030-2 uniGenes Hs.78518 gtr true cmgGene false ensemblIDs ENSG00000159899,ENST00000342694 umlsIDs C1334895 genbankNucleotideSequences 60391369,74230045,292071,167882804,21249250,27645810,511807942,3059110,187252610,18606406,148127179 geneTests true approvedGeneSymbols NPR2 geneIDs 4882 proteinSequences 5139790,4580422,578816516,3059111,187252611,530389937,530389939,167882805,119578741,167882807,119578742,167882806,119578743,119578744,18606407,113916 nextGxDx true

entryList

entry status live allelicVariantExists true epochCreated 518252400 geneMap geneSymbols IDUA, IDA sequenceID 3291 phenotypeMapList phenotypeMap phenotypeMimNumber 607014 mimNumber 252800 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 607014 phenotypeMappingKey 3 phenotype Mucopolysaccharidosis Ih phenotypeMimNumber 607015 mimNumber 252800 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 607014 phenotypeMappingKey 3 phenotype Mucopolysaccharidosis Ih/s phenotypeMimNumber 607016 mimNumber 252800 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 607014 phenotypeMappingKey 3 phenotype Mucopolysaccharidosis Is chromosomeLocationStart 980784 chromosomeSort 19 chromosomeSymbol 4 mimNumber 252800 geneInheritance None confidence P mappingMethod REa, A, S geneName Iduronidase, alpha-L- mouseMgiID MGI:96418 mouseGeneSymbol Idua computedCytoLocation 4p16.3 cytoLocation 4p16.3 transcript uc003gby.3 chromosomeLocationEnd 998316 chromosome 4 contributors Victor A. McKusick - updated : 3/31/2005 Victor A. McKusick - updated : 2/9/2004 Victor A. McKusick - updated : 11/18/2003 Kelly A. Przylepa - reorganized : 10/13/2003 Kelly A. Przylepa - updated : 10/13/2003 Victor A. McKusick - updated : 12/6/2001 George E. Tiller - updated : 4/19/2001 Victor A. McKusick - updated : 2/1/2001 Victor A. McKusick - updated : 4/21/2000 Sonja A. Rasmussen - updated : 3/2/2000 Victor A. McKusick - updated : 11/1/1999 Victor A. McKusick - updated : 9/8/1999 Victor A. McKusick - updated : 8/23/1999 Victor A. McKusick - updated : 3/12/1999 Victor A. McKusick - updated : 6/12/1998 Victor A. McKusick - updated : 2/19/1998 Victor A. McKusick - updated : 5/16/1997 externalLinks cmgGene false mgiHumanDisease false hprdIDs 02016 nbkIDs NBK1162;;Mucopolysaccharidosis Type I refSeqAccessionIDs NG_008103.1 uniGenes Hs.89560 approvedGeneSymbols IDUA nextGxDx true locusSpecificDBs http://www.LOVD.nl/IDUA;;Mendelian genes (IDUA) flybaseIDs FBgn0032343 dermAtlas false umlsIDs C1442485 gtr true geneIDs 3425 swissProtIDs P35475 zfinIDs ZDB-GENE-060526-29 ensemblIDs ENSG00000127415,ENST00000247933 geneTests true mgiIDs MGI:96418 ncbiReferenceSequences 574287321,530427350 genbankNucleotideSequences 511822373,34531242,62087381,74230020,81149502,178411,158257063,31151122,27573518,184558,20455863,71533996,148172813,148172814,1669890,21758929,78676941 proteinSequences 62087382,158257064,578808151,578808149,92090608,184559,119603022,178413,119603023,119603024,110611239,119603025,62089474,119603026,119603027,119603028,119603029,119603030,119603031,119603032,119603033,193785015 geneticsHomeReferenceIDs gene;;IDUA;;IDUA clinicalSynopsisExists false mimNumber 252800 allelicVariantList allelicVariant status live name HURLER SYNDROME dbSnps rs121965019 text {34:Scott et al. (1992)} found that 31% of MPS I alleles in a study of 64 patients with Hurler syndrome had a trp402-to-ter substitution in the alpha-L-iduronidase protein associated with very severe clinical phenotype in homozygotes. A G-to-A transition at nucleotide 1293 altered the trp-402 codon (TGG) to a stop codon (TAG); translation was terminated approximately two-thirds of the way through the 653-amino acid IDUA protein. The mutation was originally detected by chemical cleavage and then by direct PCR sequencing. The patients who were compound heterozygotes for the allele had a wide range of clinical phenotypes. Based on polymorphisms within the IDUA gene, {34:Scott et al. (1992)} determined that the trp402-to-ter mutation is associated with 3 different haplotypes, implying more than one origin for the mutation or intragenic recombination. The mutation introduced a MaeI restriction endonuclease site into the gene, thus enabling simple detection of the mutation. Assessment of the efficacy of bone marrow transplantation in patients homozygous for the mutation is thus possible. Significantly, the index case of Scheie syndrome reported by {20:McKusick et al. (1965)}, who had been assumed to be a homozygote for a separate allele at the IDUA locus, was found in fact to be a compound heterozygote for the W402X allele. Biochemically, GM1323 fibroblasts had no detectable IDUA protein using 2 different IDUA monoclonal antibodies. They had approximately 0.3% of IDUA activity. This IDUA activity must result from a mild mutation in the other MPS I allele present in the patient. Subsequently, with definition of the mutation in the other allele (see {252800.0004}), this proved to be the case. {6:Beesley et al. (2001)} found that W402X accounted for 45.3% of mutant alleles in their study. mutations IDUA, TRP402TER number 1 clinvarAccessions RCV000078374;;1;;;RCV000012683;;1 status live name HURLER SYNDROME dbSnps rs121965020 text By chemical cleavage followed by direct PCR sequencing, {33:Scott et al. (1992)} detected and characterized a nonsense mutation, a C-to-T transition at nucleotide 296, that altered a gln codon at position 70 (CAG) to a stop codon (TAG). The termination of translation occurred soon after the mature 74-kD amino terminus of the IDUA protein. Using allele-specific oligonucleotides to detect mutations in a group of 73 MPS I patients, the Q70X mutation was found to account for 15% of all MPS I alleles. The mutation was associated with an extremely severe clinical phenotype in homozygotes. Patients who were compound heterozygotes showed a wide range of clinical phenotypes. {6:Beesley et al. (2001)} found that Q70X accounted for 15.9% of alleles in their large study. mutations IDUA, GLN70TER number 2 clinvarAccessions RCV000012684;;1;;;RCV000078386;;1 status live name HURLER SYNDROME dbSnps rs121965021 text By chemical cleavage analysis followed by direct PCR sequencing, {35:Scott et al. (1992)} detected an alteration of the proline at position 533 to an arginine in the 653-amino acid alpha-L-iduronidase protein. Using allele-specific oligonucleotides to screen for the mutation in a group of 73 MPS I patients, they found that the P533R mutation accounted for 3% of alleles. Homozygotes for the P533R mutation showed an extremely severe clinical phenotype; compound heterozygotes showed a wide range of clinical phenotypes. {35:Scott et al. (1992)} found that 3 mutations, W402X, Q70X, and P533R, were responsible for 53% of MPS I alleles, which together defined 28% of MPS I genotypes. Using fluorescence-assisted mismatch analysis (FAMA) and cycle sequencing of the PCR products, {1:Alif et al. (1999)} screened for mutations in the IDUA gene in a group of 13 Moroccan patients with MPS I and their families, including 3 sibs and twin sibs. The P553R mutation, which is rare in Europeans, was identified in 92% of mutant alleles (24 of 26). This was said to be the highest frequency of this mutation detected in patients with Hurler syndrome. None of the patients carried the W402X ({252800.0001}) or the Q70X ({252800.0002}) allele, the most common MPS I mutations in Europeans. mutations IDUA, PRO533ARG number 3 clinvarAccessions RCV000012685;;1 status live name SCHEIE SYNDROME text In the fibroblast strain GM01323 derived from the index case of the Scheie syndrome ({607016}) reported by {20:McKusick et al. (1965)} and in a second cell line, GM01256, {22:Moskowitz et al. (1993)} found compound heterozygosity for the same 2 mutations: a G-to-A transition in intron 5, in position -7 from exon 6, and a W402X change (TGG to TAG) in exon 9. The latter mutation, trp402-to-ter ({252800.0001}), had previously been identified as a common MPS I mutation in the Caucasian population, present in homozygosity in some Hurler patients and in compound heterozygosity in patients with any form of MPS I, including the Scheie patient GM01323 ({34:Scott et al., 1992}). {22:Moskowitz et al. (1993)} proposed that the intron 5 mutation was responsible for the Scheie phenotype in these 2 patients. The mutation created a new acceptor splice site, causing 5 intronic nucleotides to be inserted into mRNA; this out-of-frame insertion led to an almost immediate termination codon. Additional splicing of transcripts of one or both alleles at some upstream cryptic site(s) was found. Since the normal splice site was not obliterated by the intron 5 mutation, its use would allow the synthesis of some completely normal enzyme. An analogous situation had been encountered in the HEXB gene ({268800}); mutations that create a new splice site without destroying the old one, thereby permitting expression of some functional beta-hexosaminidase, had been found in a patient with juvenile Sandhoff disease ({24:Nakano and Suzuki, 1989}) and in an individual with the asymptomatic 'hexosaminidase Paris' ({12:Dlott et al., 1990}) phenotype. Indeed, {3:Ashton et al. (1992)} and {34:Scott et al. (1992)} found a low level of immunoprecipitable alpha-L-iduronidase activity with normal K(m) and with probably normal specific activity in the Scheie fibroblast cell line GM01323. Although {19:McKusick et al. (1972)} suggested that the Scheie syndrome may represent homozygosity for a mild disease allele, based on the paradigm of hemoglobinopathies SS, CC and SC, molecular studies in lysosomal storage diseases, especially the GM2 gangliosidoses ({272800}) and Gaucher disease ({230800}), demonstrate the presence of multiple mutant alleles at each disease locus and the occurrence of compound heterozygosity as well as homozygosity in the milder phenotypes. The findings demonstrate that just one allele, if it permits residual enzyme activity, can protect from severe disease ({25:Neufeld, 1991}). Scheie syndrome must be genetically heterogeneous inasmuch as 2 other patients with this phenotype did not have the intron 5 allele. One wonders what the homozygote for this IVS5AS mutation might show phenotypically; the abnormalities might be relatively mild and late in onset, if present at all. By chemical cleavage and direct PCR sequencing, {36:Scott et al. (1993)} also found the mutation, which they referred to as 678-7g-to-a, in association with W402X in the index case of {20:McKusick et al. (1965)}. {36:Scott et al. (1993)} concluded that since the W402X allele in other combinations is associated with severe disease, the splice acceptor site mutation is likely to be responsible for the mild clinical phenotype because it allows a very small amount of normal mRNA to be produced. mutations IDUA, IVS5AS, G-A, -7 number 4 clinvarAccessions RCV000012688;;1 status live name HURLER SYNDROME dbSnps rs11934801,rs199794428 text In a patient with Hurler syndrome ({607014}) in a consanguineous Muslim Arab family in Gaza, {4:Bach et al. (1993)} observed homozygosity for an IDUA allele containing 2 amino acid substitutions: a G-to-C transversion in exon 9 converting codon 409 from GGG (gly) to CGG (arg), and an A-to-T transversion in the termination codon 654 (TGA), converting it to a cys (TGT) residue. The cDNA sequence predicted an extension of 38 amino acids before the next termination codon was reached. Both mutations were found in heterozygous form in the DNA of each parent. Expression of cDNA mutagenized at one or both positions showed that gly409-to-arg caused a reduction of less than half the alpha-L-iduronidase activity, whereas the ter-to-cys mutation reduced activity by 98% compared with expression of normal cDNA. mutations IDUA, GLY409ARG AND TER654CYS number 5 clinvarAccessions RCV000012686;;1;;;RCV000078375;;1 status live name HURLER SYNDROME dbSnps rs121965022 text {27:Schaap and Bach (1980)} found 13 Arab patients with Hurler syndrome ({607014}) but only 1 Jewish patient in Israel where ascertainment of the disorder had been complete for 15 years. The mutation in the Jewish patient was the deletion/insertion mutation described by {23:Moskowitz et al. (1993)}. The Arab patients came from 8 families, 5 of which were Druze and 3 Muslim. Unexpectedly, {4:Bach et al. (1993)} found homozygosity for 3 different mutations distributed in 7 families, 5 of them Druze: mutations in exon 2 (tyr64-to-ter), exon 7 (gln310-to-ter; {252800.0007}), and exon 8 (thr366-to-pro; {252800.0008}). Transfection of mutagenized cDNA into COS-1 cells showed that the missense mutation thr366-to-pro permitted the expression of only trace amounts of alpha-L-iduronidase activity. The nonsense mutations were associated with abnormalities of RNA processing. The tyr64-to-ter mutation was accompanied by a very low level of mRNA and skipping of exon 2. Utilization of a cryptic splice site was observed with the gln310-to-ter mutation. The Druze and Muslim Arab populations have been separated by religion since the inception of the Ismalia or Druze religion in Egypt in the 11th century A.D. At present the Druze live in a defined geographic area of southern Syria, southern Lebanon, and northern Israel; they maintain an isolated social structure with a high rate of consanguineous marriages. The Druze population in Israel numbers about 60,000. {4:Bach et al. (1993)} anticipated that MPS in the Druze population would be caused by 1 founder mutation which might or might not be shared with the Muslim patients residing in the surrounding area. They were surprised to find that, in fact, there were 3 different mutations. mutations IDUA, TYR64TER number 6 clinvarAccessions RCV000012689;;1 status live name HURLER SYNDROME dbSnps rs121965023 text See {252800.0006}. mutations IDUA, GLN310TER number 7 clinvarAccessions RCV000012690;;1 status live name HURLER SYNDROME dbSnps rs121965024 text See {252800.0006}. mutations IDUA, THR366PRO number 8 clinvarAccessions RCV000012691;;1 status live name HURLER SYNDROME text In a patient with a severe form of the Hurler syndrome, {36:Scott et al. (1993)} found that the Q70X ({252800.0002}) mutation was combined with an allele carrying a deletion of a single G residue at cDNA base 1702, resulting in a frameshift. mutations IDUA, 1-BP DEL, 1702G number 9 clinvarAccessions RCV000012687;;1 status live name HURLER SYNDROME dbSnps rs121965025 text {8:Bunge et al. (1994)} identified an R621X mutation due to a CGA-to-TGA transition in a patient with Hurler syndrome ({607014}). The patient was a compound heterozygote, the other allele being the common W402X mutation ({252800.0001}). mutations IDUA, ARG621TER number 10 clinvarAccessions RCV000012692;;1 status live name SCHEIE SYNDROME dbSnps rs121965026 text In a patient with Scheie syndrome ({607016}), {40:Tieu et al. (1995)} found a heterozygous G-to-C transversion in codon 492, corresponding to a change of arginine (CGG) to proline (CCG). The mutation, which created an ApaI site, was inherited from the patient's mother. No alpha-L-iduronidase activity was observed when cDNA mutagenized to have the R492P mutation was expressed in COS-1 cells. Even though no activity was observed, this mutation must be presumed responsible for the mild Scheie phenotype, since the other allele carried the gln70-to-ter Hurler mutation associated with severe disease ({252800.0002}). This was the third mutation to be described in the Scheie syndrome; in each case, there was compound heterozygosity for a common Hurler mutation. mutations IDUA, ARG492PRO number 11 clinvarAccessions RCV000012693;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965027 text {40:Tieu et al. (1995)} demonstrated that the Hurler/Scheie ({607015}) cell line GM00512 had a T-to-C transition in codon 490, converting leucine (CTG) to proline (CCG), and creating a SmaI site. No alpha-L-iduronidase activity was detected when cDNA containing the L490P mutation was expressed in COS-1 cells. There was no evidence for heterozygosity either in the genomic sequence or in the restriction digest, suggesting that the mutation was present in homozygous form. However, hemizygosity, because of either deletion of the IDUA gene on 1 chromosome or uniparental disomy, had not been ruled out. The GM00512 cell line was derived from a patient of Asian Indian origin, whose parents were not known to be consanguineous. Homozygosity had been observed previously only in consanguineous families or for the most common mutations, W402X ({252800.0001}) and Q70X ({252800.0002}). It is therefore possible that the L490P mutation is relatively common among Indian MPS I patients. mutations IDUA, LEU490PRO number 12 clinvarAccessions RCV000012694;;1;;;RCV000078381;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965028,rs387906504 text In a patient with Hurler/Scheie syndrome ({607015}), {40:Tieu et al. (1995)} observed a heterozygous T-to-G transversion that changed the termination codon (TGA) to glycine (GGA), which predicted an extension of 38 amino acids at the carboxyl terminus of alpha-L-iduronidase. The mutation, which created a BstNI site, was inherited from the mother. A very low level of alpha-L-iduronidase activity was observed when the mutagenized cDNA was expressed in COS-1 cells. This mutation must have been responsible for the Hurler/Scheie phenotype, as the other allele carried the Q70X Hurler mutation ({252800.0002}). Another mutation in the termination codon, X654C, had previously been observed in cells of a patient (GM01898) whose phenotype could not be clearly classified as either Hurler or Hurler/Scheie ({4:Bach et al., 1993}). mutations IDUA, TER654GLY number 13 clinvarAccessions RCV000012695;;1 status live name HURLER SYNDROME text In the study of 19 Japanese MPS I patients with various clinical phenotypes, {41:Yamagishi et al. (1996)} found that a 5-bp insertion between the T at nucleotide 704 and the C at nucleotide 705 accounted for 7 of 38 alleles (18%). This mutation had been found in no Caucasian patients. It was associated with a specific haplotype, suggesting to the authors that the individuals with the mutation derived from a common ancestor. Homozygosity of the 704ins5 mutation was associated with a severe phenotype. {15:Lee et al. (2004)} found the 705ins5 mutation in 4 of 10 unrelated Korean patients with MPS I. All occurred in compound heterozygous state in patients with Hurler syndrome ({607014}). mutations IDUA, 5-BP INS, NT704 number 14 clinvarAccessions RCV000012696;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965029 text In the study of 19 Japanese MPS I patients with various clinical phenotypes, {41:Yamagishi et al. (1996)} found that the R89Q mutation accounted for 9 of 38 alleles (24%). Homozygosity for the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for this and the 704ins5 mutation ({252800.0014}) produced an intermediate phenotype ({607015}). Haplotype analysis using polymorphisms linked to the IDUA locus demonstrated that the mutation occurred on a specific haplotype, suggesting to the authors that individuals with the mutation derived from a common ancestor. Of 3 homozygotes, 1 died of congestive heart failure at the age of 48 years. One of the heterozygotes died of the same at 31 years. She was 117 cm tall. {36:Scott et al. (1993)} had previously described the R89Q mutation in a compound heterozygous Caucasian patient. mutations IDUA, ARG89GLN number 15 clinvarAccessions RCV000012697;;1 status live name IDUA PSEUDODEFICIENCY dbSnps rs121965030 text In a healthy female, {2:Aronovich et al. (1996)} found compound heterozygosity for the W402X mutation ({252800.0001}) and a new IDUA mutation, A300T. Although fibroblasts from the patient demonstrated normal glycosaminoglycan metabolism, enzyme studies using artificial substrate showed very low levels of alpha-L-iduronidase activity. This was said to have been the first IDUA pseudodeficiency gene to be elucidated at the molecular level. mutations IDUA, ALA300THR number 16 clinvarAccessions RCV000012698;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965031 text In an 18-year-old Chinese patient with intermediate phenotype consistent with Hurler/Scheie syndrome ({607015}), {16:Lee-Chen et al. (1999)} identified homozygosity for an arg619-to-gly mutation due to a C-to-G transversion at nucleotide 1943. mutations IDUA, ARG619GLY number 17 clinvarAccessions RCV000012699;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965032 text {17:Lee-Chen and Wang (1997)} identified homozygosity for a thr364-to-met mutation in the IDUA gene product in a 10-year-old Chinese patient with the Hurler/Scheie syndrome ({607015}). mutations IDUA, THR364MET number 18 clinvarAccessions RCV000012700;;1 status live name HURLER-SCHEIE SYNDROME text In a Chinese patient with Hurler/Scheie syndrome ({607015}), {39:Teng et al. (2000)} identified compound heterozygosity for a maternal allele with a leu346-to-arg (L346R; {252800.0020}) mutation (T-to-G transversion in codon 346) and a paternal allele with a C-to-G transversion at position -3 of the 3-prime splice acceptor site of intron 2. In transfected COS-7 cells, L346R showed no appreciable IDUA activity, although it did not cause an apparent reduction in IDUA mRNA or protein level. The splice acceptor site mutation profoundly affected normal splicing leading to a very unstable mRNA. Expression of IDUA cDNA containing the mutated acceptor splice site showed trace amounts of enzyme activity (1.6% of normal activity). The results provided further support for the importance of cytosine at the -3 position in RNA processing. The patient reported by {39:Teng et al. (2000)} was 12 years old with short stature, macrocephaly, coarse face, corneal clouding, skeletal deformities, and hepatosplenomegaly, but normal intelligence. Other mild clinical features included hearing impairment, tracheal stenosis, hypertrophic cardiomyopathy, obstructive-type sleep apnea, adenoid hyperplasia, tonsil hypertrophy, umbilical hernia, anemia, mutations IDUA, IVS2AS, C-G, -3 number 19 clinvarAccessions RCV000012701;;1 status live name HURLER-SCHEIE SYNDROME dbSnps rs121965033 text See {252800.0019} and {39:Teng et al. (2000)}. {15:Lee et al. (2004)} found the L346R mutation in 6 of 10 unrelated Korean patients with MPS I, 4 with Hurler syndrome ({607014}) and 2 with Hurler/Scheie syndrome ({607015}). mutations IDUA, LEU346ARG number 20 alternativeNames HURLER SYNDROME, INCLUDED clinvarAccessions RCV000012702;;1;;;RCV000012703;;1 prefix * titles alternativeTitles IDURONIDASE, ALPHA-L preferredTitle ALPHA-L-IDURONIDASE; IDUA textSectionList textSection textSectionTitle Description textSectionContent Alpha-L-iduronidase (IDUA; {EC 3.2.1.76}), the enzyme deficient in MPS I (see {607014}, {607015}, and {607016}), hydrolyzes the terminal alpha-L-iduronic acid residues of the glycosaminoglycans dermatan sulfate and of heparan sulfate ({26:Neufeld and Muenzer, 2001}). It was originally defined as the 'Hurler corrective factor' ({5:Barton and Neufeld, 1971}). textSectionName description textSectionTitle Cloning textSectionContent {31:Scott et al. (1990)} used amino acid sequence data from purified human liver IDUA ({9:Clements et al., 1989}) to isolate both a genomic clone and a cDNA clone for IDUA. {30:Scott et al. (1991)} isolated and sequenced cDNA clones containing part of the human IDUA coding region and used PCR from reverse-transcribed RNA to obtain the full IDUA sequence. Analysis of the predicted 653-amino acid precursor protein showed that IDUA has a 26-amino acid signal peptide that is cleaved immediately before the amino terminus of the 74-kD polypeptide present in human liver IDUA. The protein sequence contains 6 potential N-glycosylation sites. Evidence of alternatively spliced mRNA from the IDUA gene was found in fibroblasts, liver, kidney, and placental RNA. textSectionName cloning textSectionTitle Gene Structure textSectionContent {33:Scott et al. (1992)} demonstrated that the IDUA gene spans approximately 19 kb and contains 14 exons. The first 2 exons are separated by an intron of 566 bp; a large intron of approximately 13 kb follows, and the last 12 exons are clustered within 4.5 kb. textSectionName geneStructure textSectionTitle Mapping textSectionContent By in situ hybridization and Southern blot analysis of mouse-human cell hybrids, {31:Scott et al. (1990)} determined that the IDUA gene maps to 4p16.3, not to chromosome 22 as earlier reported by {28,29:Schuchman et al. (1982, 1984}). {31:Scott et al. (1990)} confirmed the presence of human IDUA activity in human-mouse cell hybrids by using a monoclonal antibody specific to human IDUA. {37:Scott et al. (1992)} found that the polymorphic locus D4S111 used in the diagnosis of Huntington disease ({143100}) is the consequence of an 86-bp variable number tandem repeat (VNTR) within the IDUA gene. The gene mapped to chromosome 22 by {28,29:Schuchman et al. (1982, 1984)} by use of a polyclonal antibody in human-mouse cell hybrids may have been a crossreacting protein. {14:Grosson et al. (1994)} mapped the homologous locus in the mouse, Idua, to chromosome 5 in a continuous linkage group that included the homolog of the Huntington disease gene. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {31:Scott et al. (1990)} failed to detect major deletions or gene rearrangements in the IDUA gene in any of the 40 MPS I patients studied by Southern blot analysis. {34:Scott et al. (1992)} reported the presence of a common mutation accounting for 31% of MPS I alleles in a study of 64 MPS I patients. Chemical cleavage and then direct PCR sequencing detected the mutation. The mutation is a single base substitution that introduces a stop codon at position 402 (W402X; {252800.0001}) of the alpha-L-iduronidase protein and is associated with an extremely severe clinical phenotype in homozygotes. Patients who are compound heterozygotes having one allele carrying the W401X mutation have a wide range of clinical phenotypes. {35:Scott et al. (1992)} identified 2 additional mutations, one that introduces a stop codon at position 70 (Q70X; {252800.0002}) and the other that alters the proline at position 533 to an arginine (P533R; {252800.0003}) in the 653 amino acid alpha-L-iduronidase protein. Allele-specific oligonucleotides were used to detect the mutations in a group of 73 MPS I patients and Q70X was found to account for 15% of all MPS I alleles and P533R for 3% of MPS I alleles. Both mutations are associated with an extremely severe clinical phenotype in homozygotes. MPS I patients heterozygous for either mutation may have a wide range of clinical phenotypes. Mutations W402X ({34:Scott et al., 1992}), Q70X, and P533R accounted for 53% of MPS I alleles, which together define 28% of MPS I genotypes. {7:Bunge et al. (1995)} identified 13 novel and 7 previously reported mutations of the IDUA gene, covering 88% of mutant alleles and 86% of genotypes, in a total of 29 patients with MPS I of differing clinical severity. {32:Scott et al. (1995)} stated that 46 disease-producing mutations and 30 polymorphisms had been identified in the IDUA gene. In a mutation analysis of 85 mucopolysaccharidosis families (73 Hurler, 5 Hurler/Scheie, 7 Scheie), {6:Beesley et al. (2001)} identified 165 of the 170 mutant alleles. The 85 MPS I families were screened for 9 known mutations. W420X was the most frequent mutation in their population (43.3%) and Q70X was the second most frequent (15.9%). In 30 families, either one or both of the mutations were not identified, which accounted for 25.9% of the total alleles. All 14 exons of the alpha-L-iduronidase gene were then screened in those patients and 23 different sequence changes were found, 17 of which were previously unknown. The novel sequence changes included 4 deletions, 6 missense mutations, a splice site mutation, and a rare polymorphism. Alleles that cause the milder phenotypes, Hurler/Scheie and Scheie syndromes, are often missense mutations. {40:Tieu et al. (1995)} reported 4 novel mutations of the IDUA gene in 1 patient with the Scheie syndrome and in 3 patients with the Hurler/Scheie syndrome. The novel mutations, all single base changes, encoded the substitutions R492P ({252800.00011}) (Scheie) and X654G ({252800.0013}), P496L, and L490P ({252800.0012}) (Hurler/Scheie). The L490P mutation was apparently homozygous, whereas each of the others was found in compound heterozygosity with a Hurler mutation. The deleterious nature of the mutations was confirmed by absence of enzyme activity upon transfection of the corresponding mutagenized cDNAs into COS-1 cells. {2:Aronovich et al. (1996)} described the molecular defect underlying IDUA pseudodeficiency. The study was prompted by a patient who appeared to have, by biochemical study, both MPS I and MPS II. The common IDS mutation R468W ({309900.0012}) was found in the proband, his mother, and his sister, confirming transmission of Hunter syndrome. Additionally, the proband, his sister, and his father were found to be heterozygous for a common IDUA mutation, W402X ({252800.0001}). Notably, a new IDUA mutation, A300T ({252800.0016}), was identified in the proband, his sister, and his mother, accounting for reduced IDUA activity in these individuals. The proband's sister was asymptomatic and her cells demonstrated normal glycosaminoglycan metabolism, thus demonstrating that the W402X/A300T compound heterozygous genotype is an IDUA pseudodeficiency state. textSectionName molecularGenetics textSectionTitle Population Genetics textSectionContent {8:Bunge et al. (1994)} screened 46 European patients with mucopolysaccharidosis type I for mutations in the IDUA gene. The 2 common nonsense mutations, W402X and Q70X, were identified in 37% and 35% of mutant alleles, respectively. Considerable differences were seen in the frequency of these 2 mutations in patients from northern Europe (Norway and Finland) and other European countries (mainly the Netherlands and Germany). In Scandinavia, W402X and Q70X accounted for 17% and 62% of the MPS I alleles, respectively, whereas in other European countries W402X was about 2.5 times more frequent (48%) than Q70X (19%). {13:Gatti et al. (1997)} screened 27 Italian MPS I patients for IDUA mutations. Mutations were found in 18 patients, with 28 alleles identified. The 2 common mutations in northern Europeans (W402X and Q70X) accounted for only 11% and 13% of the alleles, respectively. The R89Q i({252800.0015}) mutation, uncommon in Europeans, was found in 1 patient, accounting for 1 of 54 alleles (1.9%). The P533R, A327P and G51D mutations accounted for 11%, 5.6%, and 9.3% of the total alleles, respectively. The P533R mutation was relatively frequent in Sicily. In a study of Israeli-Arab MPS I patients, {4:Bach et al. (1993)} identified 4 alleles, none of which had been found in Europeans. In all instances, the probands were homozygous and the parents heterozygous for the mutant alleles, as anticipated from the consanguinity in each family. One allele had 2 amino acid substitutions and was identified in a family from Gaza. The 3 single-substitution alleles were found in 7 families, 5 of them Druze, residing in a very small area of northern Israel, suggesting a founder effect. {41:Yamagishi et al. (1996)} studied mutations in the IDUA gene from 19 Japanese MPS I patients, including 2 pairs of sibs, with various clinical phenotypes (Hurler, 6 cases; Hurler/Scheie, 7 cases; Scheie, 6 cases). Two common mutations accounted for 42% of the 38 alleles in their patients: a novel 5-bp insertion (704ins5; {252800.0014}), which had not been found other populations, accounted for 18%, and an R89Q mutation, found uncommonly in Caucasians, accounted for 24%. None of the patients carried W402X or the Q79X mutations commonly found in Caucasians. Homozygosity for the 704ins5 mutation was associated with a severe phenotype, and the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for these 2 mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to the IDUA locus demonstrated that each mutation occurs on a different specific haplotype, suggesting that individuals with each of these common mutations derive from common founders. The data documented the molecular heterogeneity and racial differences in mutations in MPS I. {18:Li et al. (2002)} screened 22 unrelated MPS I patients from the United States and identified 11 different mutations in the IDUA gene, including 4 novel ones. The Q70X mutation ({252800.0002}) was found in 30% of alleles and the W402X mutation ({252800.0001}) was identified in 39% of alleles. {15:Lee et al. (2004)} performed mutation analysis of the IDUA gene in 10 unrelated Korean patients with the various clinical phenotypes of MPS I and identified 7 different mutations, 4 of which were novel. The 704ins5 mutation ({252800.0014}) was found in 4 patients and the L346R mutation ({252800.0020}) in 6. These 2 mutations accounted for half the mutations found in Korean MPS I patients. textSectionName populationGenetics textSectionTitle Animal Model textSectionContent {38:Stoltzfus et al. (1992)} cloned and characterized cDNA encoding the canine alpha-L-iduronidase and demonstrated mRNA deficiency in the MPS I dog. {21:Menon et al. (1992)} demonstrated that the canine IDUA gene has 14 exons spread over 13 kb. An unusual GC dinucleotide was found at the donor splice site of intron 11. A transcriptional start site was identified by primer extension 177 bp upstream of the initiator AUG codon. The upstream region was found to be similar to the promoter region of many housekeeping genes: it is GC rich and has 7 potential Sp1 binding sites but no TATA box or CAAT motif. The mutation in canine MPS I was found to be a G-to-A transition in the donor splice site in intron 1. The mutation caused retention of intron 1 in the RNA and created a premature termination codon at the exon-intron junction. textSectionName animalModel geneMapExists true editHistory alopez : 10/04/2012 alopez : 10/4/2012 alopez : 10/4/2012 terry : 3/5/2009 terry : 8/26/2008 carol : 11/23/2005 carol : 11/23/2005 carol : 4/5/2005 carol : 4/5/2005 wwang : 4/1/2005 terry : 3/31/2005 ckniffin : 8/4/2004 tkritzer : 2/18/2004 terry : 2/9/2004 cwells : 11/18/2003 tkritzer : 11/3/2003 carol : 10/17/2003 carol : 10/13/2003 carol : 10/13/2003 carol : 10/8/2003 carol : 10/6/2003 carol : 1/2/2002 mcapotos : 12/13/2001 terry : 12/6/2001 cwells : 5/1/2001 cwells : 4/19/2001 mcapotos : 2/12/2001 mcapotos : 2/7/2001 mcapotos : 2/6/2001 terry : 2/1/2001 mcapotos : 5/19/2000 mcapotos : 5/17/2000 terry : 4/21/2000 mcapotos : 3/3/2000 mcapotos : 3/2/2000 alopez : 11/18/1999 carol : 11/10/1999 terry : 11/1/1999 jlewis : 9/13/1999 jlewis : 9/8/1999 jlewis : 9/8/1999 terry : 8/30/1999 terry : 8/23/1999 carol : 6/11/1999 carol : 3/16/1999 terry : 3/12/1999 dholmes : 7/9/1998 terry : 6/15/1998 terry : 6/12/1998 mark : 2/25/1998 terry : 2/19/1998 mark : 5/16/1997 terry : 5/12/1997 mark : 5/15/1996 terry : 5/10/1996 mark : 4/9/1996 terry : 4/4/1996 mimman : 2/8/1996 mark : 1/25/1996 mark : 1/24/1996 terry : 1/23/1996 mark : 8/3/1995 carol : 1/13/1995 terry : 8/26/1994 jason : 7/25/1994 davew : 7/6/1994 mimadm : 4/14/1994 dateCreated Wed, 04 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/4/1986 epochUpdated 1349334000 dateUpdated Thu, 04 Oct 2012 03:00:00 EDT referenceList reference articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0003-4800&date=1999&volume=63&issue=Pt%201&spage=9 publisherName Blackwell Publishing title Mucopolysaccharidosis type I: characterization of a common mutation that causes Hurler syndrome in Moroccan subjects. mimNumber 252800 referenceNumber 1 publisherAbbreviation Blackwell pubmedID 10738517 source Ann. Hum. Genet. 63: 9-16, 1999. authors Alif, N., Hess, K., Straczek, J., Sebbar, S., N'Bou, A., Nabet, P., Dousset, B. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency. mimNumber 252800 referenceNumber 2 pubmedID 8554071 source Am. J. Hum. Genet. 58: 75-85, 1996. authors Aronovich, E. L., Pan, D., Whitley, C. B. pubmedImages false title Immunoquantification and enzyme kinetics of alpha-L-iduronidase in cultured fibroblasts from normal controls and mucopolysaccharidosis type I patients. mimNumber 252800 referenceNumber 3 pubmedID 1550122 source Am. J. Hum. Genet. 50: 787-794, 1992. authors Ashton, L. J., Brooks, D. A., McCourt, P. A. G., Muller, V. J., Clements, P. R., Hopwood, J. J. pubmedImages false title Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. mimNumber 252800 referenceNumber 4 pubmedID 8328452 source Am. J. Hum. Genet. 53: 330-338, 1993. authors Bach, G., Moskowitz, S. M., Tieu, P. T., Matynia, A., Neufeld, E. F. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=4257494 publisherName HighWire Press title The Hurler corrective factor: purification and some properties. mimNumber 252800 referenceNumber 5 publisherAbbreviation HighWire pubmedID 4257494 source J. Biol. Chem. 246: 7773-7779, 1971. authors Barton, R. W., Neufeld, E. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer.de/link/service/journals/00439/bibs/1109005/11090503.htm publisherName Springer title Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. mimNumber 252800 referenceNumber 6 publisherAbbreviation Springer pubmedID 11735025 source Hum. Genet. 109: 503-511, 2001. authors Beesley, C. E., Meaney, C. A., Greenland, G., Adams, V., Vellodi, A., Young, E. P., Winchester, B. G. pubmedImages false publisherUrl http://www.springeronline.com/ title Mucopolysaccharidosis type I: identification of 13 novel mutations of the alpha-L-iduronidase gene. mimNumber 252800 referenceNumber 7 pubmedID 7550242 source Hum. Mutat. 6: 91-94, 1995. authors Bunge, S., Kleijer, W. J., Steglich, C., Beck, M., Schwinger, E., Gal, A. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7951228 publisherName HighWire Press title Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. mimNumber 252800 referenceNumber 8 publisherAbbreviation HighWire pubmedID 7951228 source Hum. Molec. Genet. 3: 861-866, 1994. authors Bunge, S., Kleijer, W. J., Steglich, C., Beck, M., Zuther, C., Morris, C. P., Schwinger, E., Hopwood, J. J., Scott, H. S., Gal, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Immunopurification and characterization of human alpha-L-iduronidase with the use of monoclonal antibodies. mimNumber 252800 referenceNumber 9 pubmedID 2470345 source Biochem. J. 259: 199-208, 1989. authors Clements, P. R., Brooks, D. A., McCourt, P. A. G., Hopwood, J. J. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2956&date=1985&volume=152&issue=1&spage=21 publisherName Blackwell Publishing title Human alpha-L-iduronidase: 1. Purification, monoclonal antibody production, native and subunit molecular mass. mimNumber 252800 referenceNumber 10 publisherAbbreviation Blackwell pubmedID 4043081 source Europ. J. Biochem. 152: 21-28, 1985. authors Clements, P. R., Brooks, D. A., Saccone, G. T. P., Hopwood, J. J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2956&date=1985&volume=152&issue=1&spage=29 publisherName Blackwell Publishing title Human alpha-L-iduronidase: 2. Catalytic properties. mimNumber 252800 referenceNumber 11 publisherAbbreviation Blackwell pubmedID 4043083 source Europ. J. Biochem. 152: 29-34, 1985. authors Clements, P. R., Muller, V., Hopwood, J. J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2170400 publisherName HighWire Press title Two mutations produce intron insertion in mRNA and elongated beta-subunits of human beta-hexosaminidase. mimNumber 252800 referenceNumber 12 publisherAbbreviation HighWire pubmedID 2170400 source J. Biol. Chem. 265: 17921-17927, 1990. authors Dlott, B., d'Azzo, A., Quon, D. V. K., Neufeld, E. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=20&page=803 publisherName Springer title Mutations among Italian mucopolysaccharidosis type I patients. mimNumber 252800 referenceNumber 13 publisherAbbreviation Springer pubmedID 9427149 source J. Inherit. Metab. Dis. 20: 803-806, 1997. authors Gatti, R., DiNatale, P., Villani, G. R. D., Filocamo, M., Muller, V., Guo, X.-H., Nelson, P. V., Scott, H. S., Hopwood, J. J. pubmedImages false publisherUrl http://www.springeronline.com/ title Synteny conservation of the Huntington's disease gene and surrounding loci on mouse chromosome 5. mimNumber 252800 referenceNumber 14 pubmedID 7919654 source Mammalian Genome 5: 424-428, 1994. authors Grosson, C. L. S., MacDonald, M. E., Duyao, M. P., Ambrose, C. M., Roffler-Tarlov, S., Gusella, J. F. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2004&volume=66&issue=6&spage=575 publisherName Blackwell Publishing title Mutational analysis of the alpha-L-iduronidase gene in 10 unrelated Korean type I mucopolysaccharidosis patients: identification of four novel mutations. (Letter) mimNumber 252800 referenceNumber 15 publisherAbbreviation Blackwell pubmedID 15521993 source Clin. Genet. 66: 575-576, 2004. authors Lee, I. J., Hwang, S. H., Jeon, B. H., Song, S. M., Kim, J. S., Paik, K. H., Kwon, E. K., Jin, D.-K. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1999&volume=56&issue=1&spage=66 publisherName Blackwell Publishing title Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity. mimNumber 252800 referenceNumber 16 publisherAbbreviation Blackwell pubmedID 10466419 source Clin. Genet. 56: 66-70, 1999. authors Lee-Chen, G. J., Lin, S. P., Tang, Y. F., Chin, Y. W. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=9391892 publisherName HighWire Press title Mucopolysaccharidosis type I: identification of novel mutations that cause Hurler/Scheie syndrome in Chinese families. mimNumber 252800 referenceNumber 17 publisherAbbreviation HighWire pubmedID 9391892 source J. Med. Genet. 34: 939-941, 1997. authors Lee-Chen, G. J., Wang, T. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1098-3600&volume=4&issue=6&spage=420 publisherName Lippincott Williams & Wilkins title Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human (-L-iduronidase (IDUA) gene. mimNumber 252800 referenceNumber 18 publisherAbbreviation LWW pubmedID 12509712 source Genet. Med. 4: 420-426, 2002. authors Li, P., Wood, T., Thompson, J. N. pubmedImages false publisherUrl http://www.lww.com/ title Allelism, nonallelism and genetic compounds among the mucopolysaccharidoses. mimNumber 252800 referenceNumber 19 pubmedID 4112371 source Lancet 299: 993-996, 1972. Note: Originally Volume I. authors McKusick, V. A., Howell, R. R., Hussels, I. E., Neufeld, E. F., Stevenson, R. E. pubmedImages false title The genetic mucopolysaccharidoses. mimNumber 252800 referenceNumber 20 pubmedID 4221470 source Medicine 44: 445-483, 1965. authors McKusick, V. A., Kaplan, D., Wise, D., Hanley, W. B., Suddarth, S. B., Sevick, M. E., Maumanee, A. W. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(05)80182-X publisherName Elsevier Science title Architecture of the canine IDUA gene and mutation underlying canine mucopolysaccharidosis I. mimNumber 252800 referenceNumber 21 publisherAbbreviation ES pubmedID 1339393 source Genomics 14: 763-768, 1992. authors Menon, K. P., Tieu, P. T., Neufeld, E. F. pubmedImages false publisherUrl http://www.elsevier.com/ title Mutation in Scheie syndrome (MPS IS): a G-to-A transition creates new splice site in intron 5 of one IDUA allele. mimNumber 252800 referenceNumber 22 pubmedID 8318992 source Hum. Mutat. 2: 141-144, 1993. authors Moskowitz, S. M., Tieu, P. T., Neufeld, E. F. pubmedImages false title A deletion/insertion mutation in the IDUA gene in a Libyan Jewish patient with Hurler syndrome (mucopolysaccharidosis IH). mimNumber 252800 referenceNumber 23 pubmedID 8477267 source Hum. Mutat. 2: 71-73, 1993. authors Moskowitz, S. M., Tieu, P. T., Neufeld, E. F. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2522450 publisherName HighWire Press title Genetic cause of a juvenile form of Sandhoff disease: abnormal splicing of beta-hexosaminidase beta-chain gene transcript due to a point mutation within intron 12. mimNumber 252800 referenceNumber 24 publisherAbbreviation HighWire pubmedID 2522450 source J. Biol. Chem. 264: 5155-5158, 1989. authors Nakano, T., Suzuki, K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://arjournals.annualreviews.org/doi/full/10.1146/annurev.bi.60.070191.001353?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Lysosomal storage diseases. mimNumber 252800 referenceNumber 25 publisherAbbreviation ATYPON pubmedID 1883197 source Annu. Rev. Biochem. 60: 257-280, 1991. authors Neufeld, E. F. pubmedImages false publisherUrl http://www.atypon.com/ source New York: McGraw-Hill 2001. mimNumber 252800 authors Neufeld, E. F., Muenzer, J. title The mucopolysaccharidoses.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic & Molecular Bases of Inherited Disease. Vol. 2. (8th ed.) referenceNumber 26 title Incidence of mucopolysaccharidoses in Israel: is Hunter disease a 'Jewish disease'? mimNumber 252800 referenceNumber 27 pubmedID 6821579 source Hum. Genet. 56: 221-223, 1980. authors Schaap, T., Bach, G. pubmedImages false source Am. J. Hum. Genet. 34: 175A, 1982. mimNumber 252800 authors Schuchman, E. H., Astrin, K. H., Aula, P., Desnick, R. J. title Gene assignment for human alpha-L-iduronidase. (Abstract) referenceNumber 28 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6422468 publisherName HighWire Press title Regional assignment of the structural gene for human alpha-L-iduronidase. mimNumber 252800 referenceNumber 29 publisherAbbreviation HighWire pubmedID 6422468 source Proc. Nat. Acad. Sci. 81: 1169-1173, 1984. authors Schuchman, E. H., Astrin, K. H., Aula, P., Desnick, R. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1946389 publisherName HighWire Press title Human alpha-L-iduronidase: cDNA isolation and expression. mimNumber 252800 referenceNumber 30 publisherAbbreviation HighWire pubmedID 1946389 source Proc. Nat. Acad. Sci. 88: 9695-9699, 1991. authors Scott, H. S., Anson, D. S., Orsborn, A. M., Nelson, P. V., Clements, P. R., Morris, C. P., Hopwood, J. J. pubmedImages false publisherUrl http://highwire.stanford.edu title Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3. mimNumber 252800 referenceNumber 31 pubmedID 2220820 source Am. J. Hum. Genet. 47: 802-807, 1990. authors Scott, H. S., Ashton, L. J., Eyre, H. J., Baker, E., Brooks, D. A., Callen, D. F., Sutherland, G. R., Morris, C. P., Hopwood, J. J. pubmedImages false title Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. mimNumber 252800 referenceNumber 32 pubmedID 8680403 source Hum. Mutat. 6: 288-302, 1995. authors Scott, H. S., Bunge, S., Gal, A., Clarke, L. A., Morris, C. P., Hopwood, J. J. pubmedImages false title Structure and sequence of the human alpha-L-iduronidase gene. mimNumber 252800 referenceNumber 33 pubmedID 1505961 source Genomics 13: 1311-1313, 1992. authors Scott, H. S., Guo, X.-H., Hopwood, J. J., Morris, C. P. pubmedImages false title A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. mimNumber 252800 referenceNumber 34 pubmedID 1301196 source Hum. Mutat. 1: 103-108, 1992. authors Scott, H. S., Litjens, T., Hopwood, J. J., Morris, C. P. pubmedImages false title Alpha-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype. mimNumber 252800 referenceNumber 35 pubmedID 1301941 source Hum. Mutat. 1: 333-339, 1992. authors Scott, H. S., Litjens, T., Nelson, P. V., Brooks, D. A., Hopwood, J. J., Morris, C. P. pubmedImages false title Identification of mutations in the alpha-L-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes. mimNumber 252800 referenceNumber 36 pubmedID 8213840 source Am. J. Hum. Genet. 53: 973-986, 1993. authors Scott, H. S., Litjens, T., Nelson, P. V., Thompson, P. R., Brooks, D. A., Hopwood, J. J., Morris, C. P. pubmedImages false title An 86-bp VNTR within IDUA is the basis of the D4S111 polymorphic locus. mimNumber 252800 referenceNumber 37 pubmedID 1478658 source Genomics 14: 1118-1120, 1992. authors Scott, H. S., Nelson, P. V., MacDonald, M. E., Gusella, J. F., Hopwood, J. J., Morris, C. P. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1551868 publisherName HighWire Press title Cloning and characterization of cDNA encoding canine alpha-L-iduronidase: mRNA deficiency in mucopolysaccharidosis I dog. mimNumber 252800 referenceNumber 38 publisherAbbreviation HighWire pubmedID 1551868 source J. Biol. Chem. 267: 6570-6575, 1992. authors Stoltzfus, L. J., Sosa-Pineda, B., Moskowitz, S. M., Menon, K. P., Dlott, B., Hooper, L., Teplow, D. B., Shull, R. M., Neufeld, E. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2000&volume=57&issue=2&spage=131 publisherName Blackwell Publishing title Identification and characterization of -3c-g acceptor splice site mutation in human alpha-L-iduronidase associated with mucopolysaccharidosis type IH/S. mimNumber 252800 referenceNumber 39 publisherAbbreviation Blackwell pubmedID 10735634 source Clin. Genet. 57: 131-136, 2000. authors Teng, Y. N., Wang, T. R., Hwu, W. L., Lin, S. P., Lee-Chen, G. J. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S). mimNumber 252800 referenceNumber 40 pubmedID 7550232 source Hum. Mutat. 6: 55-59, 1995. authors Tieu, P. T., Bach, G., Matynia, A., Hwang, M., Neufeld, E. F. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1996)7:1<23::AID-HUMU3>3.0.CO;2-Q publisherName John Wiley & Sons, Inc. title Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. mimNumber 252800 referenceNumber 41 publisherAbbreviation Wiley pubmedID 8664897 source Hum. Mutat. 7: 23-29, 1996. authors Yamagishi, A., Tomatsu, S., Fukuda, S., Uchiyama, A., Shimozawa, N., Suzuki, Y., Kondo, N., Sukegawa, K., Orii, T. pubmedImages false publisherUrl http://www.interscience.wiley.com/ seeAlso Clements et al. (1985); Clements et al. (1985)

entryList

entry status live allelicVariantExists true epochCreated 821952000 geneMap geneSymbols EPHB2, EPHT3, DRT, ERK, PCBC, CAPB sequenceID 213 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 600997 phenotypeInheritance None phenotype {Prostate cancer/brain cancer susceptibility, somatic} phenotypeMimNumber 603688 chromosomeLocationStart 23037262 chromosomeSort 213 chromosomeSymbol 1 mimNumber 600997 geneInheritance None confidence C mappingMethod Psh, A, Fd geneName eph tyrosine kinase 3 (ephrin receptor EphB2) mouseMgiID MGI:99611 mouseGeneSymbol Ephb2 computedCytoLocation 1p36.12 cytoLocation 1p36.1-p35 transcript uc001bge.3 chromosomeLocationEnd 23241822 chromosome 1 contributors Ada Hamosh - updated : 7/6/2011 Patricia A. Hartz - updated : 2/25/2011 Ada Hamosh - updated : 2/15/2011 Ada Hamosh - updated : 8/24/2010 Matthew B. Gross - updated : 4/28/2010 Ada Hamosh - updated : 1/6/2010 Paul J. Converse - updated : 10/27/2009 Victor A. McKusick - updated : 11/20/2007 Paul J. Converse - updated : 6/14/2007 Victor A. McKusick - updated : 7/5/2006 Victor A. McKusick - updated : 9/10/2004 Cassandra L. Kniffin - updated : 5/3/2004 Stylianos E. Antonarakis - updated : 12/3/2002 Dawn Watkins-Chow - updated : 11/11/2002 Paul J. Converse - updated : 1/22/2002 Paul J. Converse - updated : 12/19/2001 Dawn Watkins-Chow - updated : 12/7/2001 Stylianos E. Antonarakis - updated : 9/25/2001 Ada Hamosh - updated : 8/1/2000 Jennifer P. Macke - updated : 1/16/1998 Mark H. Paalman - edited : 5/13/1997 Victor A. McKusick - updated : 4/4/1997 Mark H. Paalman - updated : 5/13/1996 clinicalSynopsisExists false mimNumber 600997 allelicVariantList allelicVariant status live name PROSTATE CANCER, PROGRESSION AND METASTASIS OF, SOMATIC dbSnps rs121912582 text In the prostate cancer ({603688}) cell line DU 145, derived from a brain metastasis, {17:Huusko et al. (2004)} used a combination of nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for identification of biallelic inactivation of the EPHB2 gene involving loss of the wildtype allele and a nonsense gln723-to-ter (Q723X) mutation in the other allele. The Q723X substitution arose from a 2167C-T transition. mutations EPHB2, GLN723TER number 1 clinvarAccessions RCV000009058;;1 status live name PROSTATE CANCER, PROGRESSION AND METASTASIS OF, SOMATIC dbSnps rs35882952 text In a metastatic prostate cancer ({603688}) sample, {17:Huusko et al. (2004)} discovered a heterozygous ala279-to-ser (A279S) mutation that resulted from an 835G-T transversion in the EPHB2 gene. The other allele was lost. mutations EPHB2, ALA279SER number 2 clinvarAccessions RCV000009059;;1 status live name PROSTATE CANCER, PROGRESSION AND METASTASIS OF, SOMATIC dbSnps rs28936395 text In 2 primary prostate cancers ({603688}), {17:Huusko et al. (2004)} found an asp679-to-asn (D679N) mutation that resulted from a 2035G-A transition in the EPHB2 gene. The wildtype allele was not lost. The mutation was not found in any of 246 normal controls. mutations EPHB2, ASP679ASN number 3 clinvarAccessions RCV000009060;;1 status live name PROSTATE CANCER, SUSCEPTIBILITY TO, IN AFRICAN AMERICANS, SOMATIC dbSnps rs76826147 text {22:Kittles et al. (2006)} demonstrated association between a nonsense mutation, lys1019 to stop (K1019X), in the EPHB2 gene and prostate cancer ({603688}) in African Americans. The K1019X substitution arises from a 3055A-T transition in exon 15. mutations EPHB2, LYS1019TER number 4 clinvarAccessions RCV000009061;;1 prefix * titles alternativeTitles ELK-RELATED TYROSINE KINASE; ERK;; DEVELOPMENTALLY REGULATED EPH-RELATED TYROSINE KINASE; DRT;; EPH TYROSINE KINASE 3; EPHT3;; HEK5 preferredTitle EPHRIN RECEPTOR EphB2; EPHB2 textSectionList textSection textSectionTitle Cloning textSectionContent {4:Chan and Watt (1991)} cloned partial sequences of the EEK (EPHA8; {176945}) and ERK genes encoding members of the EPH subclass of receptor protein-tyrosine kinases. Northern blot analysis of rat RNA showed that DNA encoding human ERK hybridized to transcripts most abundantly in lung. By screening a human fetal brain cDNA expression library using a monoclonal antiphosphotyrosine antibody and by 5-prime RACE (rapid amplification of cDNA ends) procedures, {18:Ikegaki et al. (1995)} isolated overlapping cDNAs encoding a receptor-type tyrosine kinase belonging to the EPH family and designated the gene DRT (for developmentally regulated EPH-related tyrosine kinase). The DRT gene is expressed in transcripts of 3 different sizes (4, 5, and 11 kb). The DRT transcripts are expressed in human brain and several other tissues, including heart, lung, kidney, placenta, pancreas, liver, and skeletal muscle, but the 11-kb DRT transcript is preferentially expressed in fetal brain. Steady-state levels of DRT mRNA in several tissues, including brain, heart, lung, and kidney, are greater in the midterm fetus than those in the adult. {18:Ikegaki et al. (1995)} showed that a large number of tumor cell lines derived from neuroectoderm express DRT transcripts. The authors speculated that DRT may play a part in human neurogenesis. Northern blot analysis by {8:Fox et al. (1995)} revealed that HEK5 is expressed as transcripts of several sizes in a variety of human tissues, with the highest level of expression in placenta. {26:Saito et al. (1995)} demonstrated from the cDNA sequence that the ERK protein has a highly hydrophobic portion upstream of the putative tyrosine kinase domain, suggesting that it possesses a receptor-like membrane-spanning structure. Using immunohistochemical analysis of the developing mouse hindbrain, {7:Cowan et al. (2000)} detected Ephb2 expression in the midline, including the floor plate and the ependymal layer. textSectionName cloning textSectionTitle Mapping textSectionContent {4:Chan and Watt (1991)} mapped the EEK and ERK genes to chromosome 1 by Southern blot analysis of somatic cell hybrids. {18:Ikegaki et al. (1995)} mapped DRT, the EPHB2 gene, to 1p36.1-p35 by PCR screening of human/rodent somatic cell hybrid panels and by fluorescence in situ hybridization. As the distal end of 1p is often deleted in neuroblastomas, the DRT gene may play a role in neuroblastoma and small cell lung carcinoma (SCLC) tumorigenesis. By fluorescence in situ hybridization, {26:Saito et al. (1995)} demonstrated that the ERK gene is located in chromosomal region 1p36.1. They showed that the homologous genes are located on mouse 4D2.2-D3 and rat 5q36.13, both of which are regions with conserved linkage homology to human chromosome 1p. textSectionName mapping textSectionTitle Gene Function textSectionContent Using a yeast 2-hybrid system, {7:Cowan et al. (2000)} demonstrated that PDZ domain-containing protein Pick1 (PRKCABP; {605926}) binds the C-terminal tail of EphB2. Using colocalization studies and biochemical analysis, they demonstrated that a protein complex containing EphB2 and aquaporin-1 (AQP1; {107776}) is formed in vivo. They concluded that Ephb2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water. By treating embryonic rat cortical neurons with Efnb2 ({600527}), followed by stimulation with glutamate, {27:Takasu et al. (2002)} observed a large increase in intracellular calcium that was dependent on the cytoplasmic domain of the ephrin receptor Ephb2. Treatment with Bdnf ({113505}) did not result in an increase in glutamate-stimulated intracellular calcium. Western blot analysis showed that Efnb2 treatment increased tyrosine phosphorylation of NMDA receptor 2B (Nr2b, or Grin2b; {138252}) at positions 1252, 1336, and 1472 by the Src family tyrosine kinase Fyn ({137025}). Efnb2 treatment also increased phosphorylation of Creb ({123810}) at ser133, which was mediated by the NMDA receptor. In addition, Efnb2 treatment potentiated glutamate activation of Bdnf and Cpg15. {27:Takasu et al. (2002)} concluded that the EFNB-EPHB-NMDA receptor interaction may represent an early step in the initiation of synapse formation or maturation and may potentiate the ability of the NMDA receptor to respond to activity-dependent signals from the extracellular milieu. In a perspective, {9:Ghosh (2002)} noted that {10:Grunwald et al. (2001)} and {12:Henderson et al. (2001)} reported that mice lacking Ephb2 had defective synaptic plasticity, particularly at CA1 synapses, possibly due to a lack of proper clustering of NMDA receptors at the synapse. {25:Murai and Pasquale (2002)} reviewed evidence that Eph receptors function in modifying the strength of existing synapses in the adult brain. Morphologic changes in dendritic spines are believed to be caused by dynamic regulation of actin polymerization. {19:Irie and Yamaguchi (2002)} found that the EphB2 receptor tyrosine kinase physically associates with the guanine nucleotide exchange factor intersectin-1 ({602442}) in cooperation with the actin-regulating protein N-WASP ({605056}), which in turn activates the Rho family GTPase Cdc42 ({116952}) and spine morphogenesis. EPHB receptor tyrosine kinases are involved in formation and remodeling of dendritic spines, which receive the majority of excitatory synaptic inputs in the brain. Using immunoprecipitation, Western blot, and immunocytochemical analyses {28:Tolias et al. (2007)} showed that the PH domain, coiled-coil domain, and an adjacent region of TIAM1 ({600687}) interacted with EPHB2. The interaction led to phosphorylation and recruitment of TIAM1 to EPHB complexes containing NMDA glutamate receptors. Mutation and RNA interference analyses revealed that disruption of TIAM1 function blocked EPHB2-induced spine formation. {28:Tolias et al. (2007)} proposed that EPHB receptors regulate spine development, in part, by recruiting and activating TIAM1, which leads to RAC1 ({602048})-dependent actin remodeling required for spine formation. {3:Batlle et al. (2002)} showed that beta-catenin (CTNNB1; {116806}) and TCF (see TCF7L2; {602228}) inversely control the expression of the EphB2/EphB3 ({601839}) receptors and their ligand, ephrin B1 (EFNB1; {300035}), in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes revealed that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3 null mice, the proliferative and differentiated populations intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their downward migratory path, but scattered along crypt and villus. The authors concluded that, in the intestinal epithelium, beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin B system. {14:Himanen et al. (2004)} found that ephrin-A5 ({601535}) binds to the EphB2 receptor, leading to receptor clustering, autophosphorylation, and initiation of downstream signaling. Ephrin-A5 induced EphB2-mediated growth cone collapse and neurite retraction in a model system. X-ray crystallography confirmed the interaction and showed that the ephrin-A5-EphB2 complex is a heterodimer. {14:Himanen et al. (2004)} emphasized the unexpected finding of crosstalk between A- and B-subclass Eph receptors and ephrins. Using gain- and loss-of-function experiments in mice, {16:Holmberg et al. (2006)} found that EphB receptors, in addition to directing cell migration, regulated proliferation in the intestine. EphB2 and EphB3 kinase-dependent signaling promoted cell cycle reentry of intestinal progenitor cells and accounted for about 50% of the mitogenic activity in adult mouse small intestine and colon. {16:Holmberg et al. (2006)} concluded EphB receptors are key coordinators of migration and proliferation in the intestinal stem cell niche. The EPHB2 and EPHB3 genes are targets of beta-catenin and TCF4 ({602272}) in colorectal cancer (CRC; {114500}) and in normal intestinal cells. In the intestinal epithelium, ephrin-B signaling controls the positioning of cell types along the crypt-villus axis. In CRC, ephrin-B activity suppresses tumor progression beyond the earliest stages. {6:Cortina et al. (2007)} showed that EphB receptors compartmentalize the expansion of CRC cells through a mechanism depending on adhesion mediated by E-caderin (CDH1; {192090}). They demonstrated that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1-positive territories in vitro and in vivo. At the onset of tumorigenesis, CRC cells must silence EphB expression to avoid repulsive interactions imposed by intestinal cells normally expressing ephrin-B1 ({300035}). {21:Jorgensen et al. (2009)} implemented a proteomic strategy to systematically determine cell-specific signaling networks underlying EphB2- and ephrin-B1-controlled cell sorting. Quantitative mass spectrometric analysis of mixed populations of EphB2- and ephrin-B1-expressing cells that were labeled with different isotopes revealed cell-specific tyrosine phosphorylation events. Functional associations between these phosphotyrosine signaling networks and cell sorting were established with small interfering RNA screening. Data-driven network modeling revealed that signaling between mixed EphB2- and ephrin-B1-expressing cells is asymmetric and that the distinct cell types use different tyrosine kinases and targets to process signals induced by cell-cell contact. {21:Jorgensen et al. (2009)} provided systems- and cell-specific network models of contact-initiated signaling between 2 distinct cell types. {5:Cisse et al. (2011)} showed that amyloid-beta (see {104760}) oligomers bind to the fibronectin repeat domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer disease and related models, they used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centers of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation, important for memory formation, in the dentate gyrus. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, {5:Cisse et al. (2011)} concluded that depletion of EphB2 is critical in amyloid-beta-induced neuronal dysfunction, and suggests that increasing EphB2 levels or function could be beneficial in Alzheimer disease. {23:Margolis et al. (2010)} showed that the mouse Rhoa ({165390}) guanine nucleotide exchange factor ephexin-5 (E5, or ARHGEF15; {608504}) specifically coimmunoprecipitated with Ephb2. Knockdown and overexpression studies revealed that binding of E5 to Ephb2 inhibited formation of excitatory synapses. The E5-Ephb2 interaction was terminated by the binding of ephrin B to Ephb2. Activation of Ephb2 by ephrin B resulted in tyrosine phosphorylation, release, and destabilization of E5, permitting formation of additional excitatory synapses. {2:Attwood et al. (2011)} demonstrated in mice that the serine protease neuropsin ({605644}) is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2-NMDA receptor interaction, the expression of Fkbp5 ({602623}), and anxiety-like behavior. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala, causing dissociation of EphB2 from the NR1 ({138249}) subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkpb5 gene expression, and enhances behavioral signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1, resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene, and low anxiety. The behavioral response to stress can be restored by intraamygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wildtype mice. {2:Attwood et al. (2011)} concluded that their findings established a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent Crystal Structure {29:Wybenga-Groot et al. (2001)} reported the x-ray crystal structure of an autoinhibited, unphosphorylated form of EphB2 composed of the juxtamembrane region and the kinase domain at 1.9-angstrom resolution. The structure, supported by mutagenesis data, revealed that the juxtamembrane segment adopts a helical conformation that distorts the small lobe of the kinase domain and blocks the activation segment from attaining an activated conformation. {29:Wybenga-Groot et al. (2001)} stated that phosphorylation of conserved juxtamembrane tyrosines would relieve this autoinhibition by disturbing the association of the juxtamembrane segment with the kinase domain, while liberating phosphotyrosine sites for binding SH2 domains of target proteins. EPHB receptors bind to and are activated by the transmembrane B-ephrins, resulting in the formation of discrete bidirectional signaling centers in which the EPH receptor tyrosine kinase domain transduces the forward signal into its cell and the ephrin transduces the reverse signal into its cell. {15:Himanen et al. (2001)} reported the crystal structure of the N-terminal ligand-binding globular domain of EPHB2 bound to the complete extracellular domain of EFNB2 at 2.7-angstrom resolution. The overall structure of each molecule in the complex is similar to that seen in the unbound molecule. Binding occurs through an expansive dimerization interface dominated by the insertion of an extended ephrin loop into a channel at the surface of the receptor. The EPHB-EFNB dimers then join to form a stable tetramer in which each molecule interacts with 2 complementary molecules, allowing transautophosphorylation and signal initiation. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent {17:Huusko et al. (2004)} combined emetine inhibition of nonsense-mediated decay (NMD) and microarray analysis with comparative genomic hybridization (CGH) to screen prostate cancer-derived cell lines for transcripts that undergo NMD and are transcribed from genes with deletions on both alleles. This way they could identify genes with inactivation of the 1 allele by a nonsense mutation and loss of the outer allele through deletion. They identified previously unknown mutations in the EPHB2 gene. The DU 145 prostate cancer cell line, originating from a brain metastasis, was found to carry a truncating mutation of EPHB2 ({600997.0001}) and a deletion of the remaining allele. Additional frameshift, splice site, missense, and nonsense mutations were present in clinical prostate cancer samples. Transfection of DU 145 cells, which lack functional EPHB2, with wildtype EPHB2 suppressed clonogenic growth. These studies indicated that EPHB2 may have an essential role in cell migration and maintenance of normal tissue architecture and that mutational inactivation of the EPHB2 gene may be important in the progression and metastasis of prostate cancer. {24:Mercola and Welsh (2004)} reviewed the combination of methods, emetine suppression of NMD and microarray analysis with CGH, for identifying disease-gene associations. As many as one-third of inherited disorders are caused by mutations that disrupt reading frames. {22:Kittles et al. (2006)} performed direct sequencing of the coding region of EPHB2 in 72 probands from the African American Hereditary Prostate Cancer Study. They found the K1019X (3055A-T; {600997.0004}) mutation in 15.3% of the African American probands but in only 1.7% of 231 European American control samples. The T allele was significantly more common among African American probands (15.3%) than among African American male controls (5.2%) (odds ratio = 3.31). In order to rule out a spurious association of K1019X with prostate cancer in African Americans due to admixture stratification, {22:Kittles et al. (2006)} controlled for ancestral differences between prostate cancer cases and controls by estimating individual ancestry for each subject using 34 ancestry-informative markers (AIMs). Individual West African ancestry ranged from 10% to 93.5% with a mean estimate of 71.3%. The estimates for West African ancestry for the controls ranged from 6.5% to 95.3%. After testing for individual ancestry, the association of EPHB2 K10X probands compared with African American healthy controls was still significant (p = 0.01). {20:Johnson et al. (2010)} identified subgroups of human ependymoma ({137800}) and then performed genomic analyses and found subgroup-specific alterations that included amplifications and homozygous deletions of genes not previously implicated in ependymoma. They then used cross-species genomics to select cellular compartments most likely to give rise to subgroups of ependymoma and compared human tumors and mouse neural stem cells, isolated from different regions, specifically with an intact or deleted Cdkn2a ({600160})/Cdkn2b ({600431}) locus. The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted CDKN2A/CDKN2B matched only that of embryonic cerebral Cdkn2a/Cdkn2b -/- mouse neuronal stem cells. Activation of Ephb2 signaling in Cdkn2a/Cdkn2b -/- mouse neuronal stem cells, but not other neural stem cells, generated the first mouse model of ependymoma, which was highly penetrant and accurately modeled the histology and transcriptome of 1 subgroup of human supratentorial tumor (subgroup D). Comparative analysis of matched mouse and human tumors revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {11:Halford et al. (2000)} generated mice deficient in Ryk ({600524}) and found that they had a distinctive craniofacial appearance, shortened limbs, and postnatal mortality due to feeding and respiratory complications associated with a complete cleft of the secondary palate. Consistent with cleft palate phenocopy in Ephb2/Ephb3-deficient mice and the role of a Drosophila Ryk ortholog, 'Derailed,' in the transduction of repulsive axon pathfinding cues, biochemical data implicated Ryk in signaling mediated by Eph receptors and cell junction-associated Af6 ({159559}). {11:Halford et al. (2000)} concluded that their findings highlighted the importance of signal crosstalk between members of different RTK subfamilies. {13:Henkemeyer et al. (1996)} generated 2 different lines of mice lacking Ephb2, which they called Nuk1: a null allele and an allele that encodes a beta-gal fusion receptor lacking the tyrosine kinase and C-terminal domains. By analyzing brains from homozygous mutant mice, they demonstrated that the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the 2 temporal lobes. {13:Henkemeyer et al. (1996)} concluded that Ephb2, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system. {7:Cowan et al. (2000)} detected a strain-specific circling behavior associated with abnormal vestibular function in the Ephb2 knockout mutant mice generated by {13:Henkemeyer et al. (1996)}. In mutant embryos, the contralateral inner ear efferent growth cones exhibited inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals was severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells showed ultrastructural defects in the mutants. A molecular link to fluid regulation was provided by the demonstration that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. {7:Cowan et al. (2000)} suggested that EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water. {1:Alfaro et al. (2008)} observed significantly reduced thymic cellularity in both double-negative (DN; CD4 ({186940})-negative/CD8 (see {186910})-negative) and double-positive cells in Ephb2- and/or Ephb3-deficient mice. Adult mutant thymuses had increased proportions of DN cells without significant variation in the percentage of other subsets. Thymocyte number decreased significantly in all compartments from the DN3 (CD44 ({107269})-negative/CD25 ({147730})-positive) stage onward, without variation in the numbers of either DN1 (CD44-positive/CD25-negative) or DN2 (CD44-positive/CD25-positive) cells. {1:Alfaro et al. (2008)} observed the same changes in day-15 fetal Ephb2- and/or Ephb3-deficient thymi and proposed that the adult phenotype results from the gradual accumulation of defects appearing early in ontogeny. textSectionName animalModel geneMapExists true editHistory carol : 08/01/2014 carol : 8/1/2014 carol : 12/11/2012 carol : 4/12/2012 alopez : 7/7/2011 alopez : 7/7/2011 terry : 7/6/2011 mgross : 4/6/2011 terry : 2/25/2011 alopez : 2/18/2011 terry : 2/15/2011 mgross : 8/24/2010 terry : 8/24/2010 alopez : 6/30/2010 terry : 6/30/2010 wwang : 5/5/2010 mgross : 4/28/2010 alopez : 1/15/2010 terry : 1/6/2010 mgross : 10/29/2009 terry : 10/27/2009 alopez : 12/7/2007 terry : 11/20/2007 mgross : 6/14/2007 alopez : 7/7/2006 terry : 7/5/2006 alopez : 9/16/2004 alopez : 9/15/2004 alopez : 9/14/2004 terry : 9/10/2004 tkritzer : 5/3/2004 ckniffin : 5/3/2004 tkritzer : 3/14/2003 ckniffin : 3/5/2003 mgross : 12/3/2002 carol : 11/11/2002 mgross : 1/22/2002 alopez : 12/19/2001 alopez : 12/19/2001 carol : 12/12/2001 terry : 12/7/2001 mgross : 9/25/2001 alopez : 8/1/2000 psherman : 4/23/1998 psherman : 4/21/1998 psherman : 4/20/1998 dholmes : 1/16/1998 dholmes : 1/16/1998 jenny : 4/4/1997 joanna : 1/23/1996 mark : 1/19/1996 dateCreated Thu, 18 Jan 1996 03:00:00 EST creationDate Victor A. McKusick : 1/18/1996 epochUpdated 1406876400 dateUpdated Fri, 01 Aug 2014 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1111/j.1365-2567.2008.02828.x publisherName Blackwell Publishing title Alterations in the thymocyte phenotype of EphB-deficient mice largely affect the double negative cell compartment. mimNumber 600997 referenceNumber 1 publisherAbbreviation Blackwell pubmedID 18397270 source Immunology 125: 131-143, 2008. authors Alfaro, D., Munoz, J. J., Garcia-Ceca, J., Cejalvo, T., Jimenez, E., Zapata, A. pubmedImages true publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1038/nature09938 publisherName Nature Publishing Group title Neuropsin cleaves EphB2 in the amygdala to control anxiety. mimNumber 600997 referenceNumber 2 publisherAbbreviation NPG pubmedID 21508957 source Nature 473: 372-375, 2011. authors Attwood, B. K., Bourgognon, J.-M., Patel, S., Mucha, M., Schiavon, E., Skrzypiec, A. E., Young, K. W., Shiosaka, S., Korostynski, M., Piechota, M., Przewlocki, R., Pawlak, R. pubmedImages true publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092867402010152 publisherName Elsevier Science title Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB. mimNumber 600997 referenceNumber 3 publisherAbbreviation ES pubmedID 12408869 source Cell 111: 251-263, 2002. authors Batlle, E., Henderson, J. T., Beghtel, H., van den Born, M. M. W., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T., Clevers, H. pubmedImages false publisherUrl http://www.elsevier.com/ title Eek and erk, new members of the eph subclass of receptor protein-tyrosine kinases. mimNumber 600997 referenceNumber 4 pubmedID 1648701 source Oncogene 6: 1057-1061, 1991. authors Chan, J., Watt, V. M. pubmedImages false articleUrl http://dx.doi.org/10.1038/nature09635 publisherName Nature Publishing Group title Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. mimNumber 600997 referenceNumber 5 publisherAbbreviation NPG pubmedID 21113149 source Nature 469: 47-52, 2011. authors Cisse, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., Ho, K., Yu, G.-Q., Mucke, L. pubmedImages true publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng.2007.11 publisherName Nature Publishing Group title EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. mimNumber 600997 referenceNumber 6 publisherAbbreviation NPG pubmedID 17906625 source Nature Genet. 39: 1376-1383, 2007. authors Cortina, C., Palomo-Ponce, S., Iglesias, M., Fernandez-Masip, J. L., Vivancos, A., Whissell, G., Huma, M., Peiro, N., Gallego, L., Jonkheer, S., Davy, A., Lloreta, J., Sancho, E., Batlle, E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)81174-5 publisherName Elsevier Science title EphB2 guides axons at the midline and is necessary for normal vestibular function. mimNumber 600997 referenceNumber 7 publisherAbbreviation ES pubmedID 10839360 source Neuron 26: 417-430, 2000. authors Cowan, C. A., Yokoyama, N., Bianchi, L. M., Henkemeyer, M., Fritzsch, B. pubmedImages false publisherUrl http://www.elsevier.com/ title cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases. mimNumber 600997 referenceNumber 8 pubmedID 7898931 source Oncogene 10: 897-905, 1995. authors Fox, G. M., Holst, P. L., Chute, H. T., Lindberg, R. A., Janssen, A. M., Basu, R., Welcher, A. A. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11799227 publisherName HighWire Press title Learning more about NMDA receptor regulation. mimNumber 600997 referenceNumber 9 publisherAbbreviation HighWire pubmedID 11799227 source Science 295: 449-451, 2002. authors Ghosh, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(01)00550-5 publisherName Elsevier Science title Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. mimNumber 600997 referenceNumber 10 publisherAbbreviation ES pubmedID 11754835 source Neuron 32: 1027-1040, 2001. authors Grunwald, I. C., Korte, M., Wolfer, D., Wilkinson, G. A., Unsicker, K., Lipp, H.-P., Bonhoeffer, T., Klein, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/78099 publisherName Nature Publishing Group title Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. mimNumber 600997 referenceNumber 11 publisherAbbreviation NPG pubmedID 10932185 source Nature Genet. 25: 414-418, 2000. authors Halford, M. M., Armes, J., Buchert, M., Meskenaite, V., Grail, D., Hibbs, M. L., Wilks, A. F., Farlie, P. G., Newgreen, D. F., Hovens, C. M., Stacker, S. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0896-6273(01)00553-0 publisherName Elsevier Science title The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. mimNumber 600997 referenceNumber 12 publisherAbbreviation ES pubmedID 11754836 source Neuron 32: 1041-1056, 2001. authors Henderson, J. T., Georgiou, J., Jia, Z., Robertson, J., Elowe, S., Roder, J. C., Pawson, T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80075-6 publisherName Elsevier Science title Nuk controls pathfinding of commissural axons in the mammalian central nervous system. mimNumber 600997 referenceNumber 13 publisherAbbreviation ES pubmedID 8689685 source Cell 86: 35-46, 1996. authors Henkemeyer, M., Orioli, D., Henderson, J. T., Saxton, T. M., Roder, J., Pawson, T., Klein, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nn1237 publisherName Nature Publishing Group title Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. mimNumber 600997 referenceNumber 14 publisherAbbreviation NPG pubmedID 15107857 source Nature Neurosci. 7: 501-509, 2004. authors Himanen, J.-P., Chumley, M. J., Lackmann, M., Li, C., Barton, W. A., Jeffrey, P. D., Vearing, C., Geleick, D., Feldheim, D. A., Boyd, A. W., Henkemeyer, M., Nikolov, D. B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/414933a publisherName Nature Publishing Group title Crystal structure of an Eph receptor-ephrin complex. mimNumber 600997 referenceNumber 15 publisherAbbreviation NPG pubmedID 11780069 source Nature 414: 933-938, 2001. authors Himanen, J.-P., Rajashankar, K. R., Lackmann, M., Cowan, C. A., Henkemeyer, M., Nikolov, D. B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(06)00579-4 publisherName Elsevier Science title EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. mimNumber 600997 referenceNumber 16 publisherAbbreviation ES pubmedID 16777604 source Cell 125: 1151-1163, 2006. authors Holmberg, J., Genander, M., Halford, M. M., Anneren, C., Sondell, M., Chumley, M. J., Silvany, R. E., Henkemeyer, M., Frisen, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng1408 publisherName Nature Publishing Group title Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. mimNumber 600997 referenceNumber 17 publisherAbbreviation NPG pubmedID 15300251 source Nature Genet. 36: 979-983, 2004. authors Huusko, P., Ponciano-Jackson, D., Wolf, M., Kiefer, J. A., Azorsa, D. O., Tuzmen, S., Weaver, D., Robbins, C., Moses, T., Allinen, M., Hautaniemi, S., Chen, Y., {and 14 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8589679 publisherName HighWire Press title Molecular characterization and chromosomal localization of DRT (EPHT3): a developmentally regulated human protein-tyrosine kinase gene of the EPH family. mimNumber 600997 referenceNumber 18 publisherAbbreviation HighWire pubmedID 8589679 source Hum. Molec. Genet. 4: 2033-2045, 1995. authors Ikegaki, N., Tang, X. X., Liu, X.-G., Biegel, J. A., Allen, C., Yoshioka, A., Sulman, E. P., Brodeur, G. M., Pleasure, D. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nn964 publisherName Nature Publishing Group title EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. mimNumber 600997 referenceNumber 19 publisherAbbreviation NPG pubmedID 12389031 source Nature Neurosci. 5: 1117-1118, 2002. authors Irie, F., Yamaguchi, Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature09173 publisherName Nature Publishing Group title Cross-species genomics matches driver mutations and cell compartments to model ependymoma. mimNumber 600997 referenceNumber 20 publisherAbbreviation NPG pubmedID 20639864 source Nature 466: 632-636, 2010. authors Johnson, R. A., Wright, K. D., Poppleton, H., Mohankumar, K. M., Finkelstein, D., Pounds, S. B., Rand, V., Leary, S. E. S., White, E., Eden, C., Hogg, T., Northcott, P., {and 17 others} pubmedImages true publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=20007894 publisherName HighWire Press title Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells. mimNumber 600997 referenceNumber 21 publisherAbbreviation HighWire pubmedID 20007894 source Science 326: 1502-1509, 2009. authors Jorgensen, C., Sherman, A., Chen, G. I., Pasculescu, A., Poliakov, A., Hsiung, M., Larsen, B., Wilkinson, D. G., Linding, R., Pawson, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16155194 publisherName HighWire Press title A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. mimNumber 600997 referenceNumber 22 publisherAbbreviation HighWire pubmedID 16155194 source J. Med. Genet. 43: 507-511, 2006. authors Kittles, R. A., Baffoe-Bonnie, A. B., Moses, T. Y., Robbins, C. M., Ahaghotu, C., Huusko, P., Pettaway, C., Vijayakumar, S., Bennett, J., Hoke, G., Mason, T., Weinrich, S., Trent, J. M., Collins, F. S., Mousses, S., Bailey-Wilson, J., Furbert-Harris, P., Dunston, G., Powell, I. J., Carpten, J. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(10)01124-4 publisherName Elsevier Science title EphB-mediated degradation of the RhoA GEF ephexin5 relieves a developmental brake on excitatory synapse formation. mimNumber 600997 referenceNumber 23 publisherAbbreviation ES pubmedID 21029865 source Cell 143: 442-455, 2010. authors Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., Soskis, M. J., Sahin, M., Greenberg, M. E. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng0904-937 publisherName Nature Publishing Group title From mRNA to tumor suppressor. (Commentary) mimNumber 600997 referenceNumber 24 publisherAbbreviation NPG pubmedID 15340430 source Nature Genet. 36: 937-938, 2004. authors Mercola, D., Welsh, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0896627302005652 publisherName Elsevier Science title Can Eph receptors stimulate the mind? mimNumber 600997 referenceNumber 25 publisherAbbreviation ES pubmedID 11804564 source Neuron 33: 159-162, 2002. authors Murai, K. K., Pasquale, E. B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0888-7543(95)80224-A publisherName Elsevier Science title Identification of the human ERK gene as a putative receptor tyrosine kinase and its chromosomal localization to 1p36.1: a comparative mapping of human, mouse, and rat chromosomes. mimNumber 600997 referenceNumber 26 publisherAbbreviation ES pubmedID 7601466 source Genomics 26: 382-384, 1995. authors Saito, T., Seki, N., Matsuda, Y., Kitahara, M., Murata, M., Kanda, N., Nomura, N., Yamamoto, T., Hori, T. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11799243 publisherName HighWire Press title Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. mimNumber 600997 referenceNumber 27 publisherAbbreviation HighWire pubmedID 11799243 source Science 295: 491-495, 2002. authors Takasu, M. A., Dalva, M. B., Zigmond, R. E., Greenberg, M. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17440041 publisherName HighWire Press title The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. mimNumber 600997 referenceNumber 28 publisherAbbreviation HighWire pubmedID 17440041 source Proc. Nat. Acad. Sci. 104: 7265-7270, 2007. authors Tolias, K. F., Bikoff, J. B., Kane, C. G., Tolias, C. S., Hu, L., Greenberg, M. E. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(01)00496-2 publisherName Elsevier Science title Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. mimNumber 600997 referenceNumber 29 publisherAbbreviation ES pubmedID 11572780 source Cell 106: 745-757, 2001. authors Wybenga-Groot, L. E., Baskin, B., Ong, S. H., Tong, J., Pawson, T., Sicheri, F. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:99611 mgiHumanDisease false ncbiReferenceSequences 530360905,530360907,530360901,530360903,111118979,111118977 refSeqAccessionIDs NG_011804.1 dermAtlas false hprdIDs 02997 swissProtIDs P29323 zfinIDs ZDB-GENE-050522-415,ZDB-GENE-070713-2 uniGenes Hs.523329 gtr true cmgGene false ensemblIDs ENSG00000133216,ENST00000400191 umlsIDs C1333340 genbankNucleotideSequences 21765453,148132304,29329531,148132305,2739055,511873035,6165330,511873038,25136946,1060894,511873041,29466516,285916,1100109,27371007,45709657,19387973,194385205,45705823,194389169,148921799,39644788,71514991,307334908,17065706,551609,31222,68533090,495677,218055939 geneTests false approvedGeneSymbols EPHB2 geneIDs 2048 proteinSequences 29329532,1060895,76803654,2739056,285917,111118978,1100110,21396504,194385206,45709658,119615429,194389170,119615428,119615431,119615430,148921800,119615432,307334909,578798608,578798606,551610,68533091,31223,495678,218055940 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 707554800 geneMap geneSymbols TAP1, ABCB2, TAP1, RING4, PSF1 sequenceID 4886 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 170260 phenotypeInheritance Autosomal recessive phenotype Bare lymphocyte syndrome, type I phenotypeMimNumber 604571 chromosomeLocationStart 32812985 chromosomeSort 337 chromosomeSymbol 6 mimNumber 170260 geneInheritance None confidence C mappingMethod REn geneName Transporter 1, ATP-binding cassette, subfamily B comments ~7kb telomeric to TAP2 mouseMgiID MGI:98483 mouseGeneSymbol Tap1 computedCytoLocation 6p21.32 cytoLocation 6p21.3 transcript uc003ocg.3 chromosomeLocationEnd 32821747 chromosome 6 contributors Paul J. Converse - updated : 1/11/2006 Marla J. F. O'Neill - updated : 7/13/2005 Victor A. McKusick - updated : 8/1/2001 Ada Hamosh - updated : 1/5/2001 Victor A. McKusick - updated : 4/8/1997 clinicalSynopsisExists false mimNumber 170260 allelicVariantList allelicVariant status live name PEPTIDE TRANSPORTER PSF1 POLYMORPHISM dbSnps rs1057141 text By SSCP followed by DNA sequencing, {3:Colonna et al. (1992)} identified an A-to-G transition at nucleotide 1069 in the PSF1 gene, changing isoleucine-333 to valine. mutations TAP1, ILE333VAL number 1 clinvarAccessions RCV000014732;;1 status live name PEPTIDE TRANSPORTER PSF1 POLYMORPHISM dbSnps rs1135216 text By SSCP analysis followed by DNA sequencing, {3:Colonna et al. (1992)} identified an A-to-G transition at nucleotide 1982 in segment 8 of the PSF1 gene, replacing asp-637 with glycine. The allele designated PSF1A showed linkage of ile-333 and asp-637; val-333 together with gly-637 or asp-637 form the PSF1B and PSF1C alleles, respectively. mutations TAP1, ASP637GLY number 2 clinvarAccessions RCV000014733;;1 status live name TAP1 DEFICIENCY, SOMATIC dbSnps rs121917702 text In a human small cell lung cancer cell line, {2:Chen et al. (1996)} identified heterozygosity for an R659Q allele at the TAP1 locus. Only the R659Q allele was transcribed into RNA. Even though the protein was expressed, the cells acted as if they were TAP-deficient and were restored to normal by transfection of a functional TAP1 allele. Thus the cells had a defect in the conveying of intracellular peptides into the endoplasmic reticulum for complex formation with class I MHC and subsequent recognition by cytotoxic T lymphocytes. mutations TAP1, ARG659GLN number 3 clinvarAccessions RCV000014734;;1 status live name BARE LYMPHOCYTE SYNDROME, TYPE I text In a 46-year-old Japanese woman originally reported by {10:Maeda et al. (1985)} with type I bare lymphocyte syndrome ({604571}), {6:Furukawa et al. (1999)} identified homozygosity for a G-to-A transition at basepair 536 in intron 1 of the TAP1 gene. This resulted in an altered splice acceptor site and deletion of a G in codon 200 of mRNA, causing a frameshift and a premature stop codon at 228. The patient's first-cousin parents and other family members were heterozygous for the mutation. mutations TAP1, IVS1, G-A, -1 number 4 clinvarAccessions RCV000014735;;1 prefix * titles alternativeTitles TRANSPORTER, ABC, MHC, 1;; ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 2; ABCB2;; ATP-BINDING CASSETTE TRANSPORTER, MAJOR HISTOCOMPATIBILITY COMPLEX, 1;; ABC TRANSPORTER, MHC, 1;; PEPTIDE TRANSPORTER PSF1;; TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING 1;; PEPTIDE SUPPLY FACTOR 1; PSF1;; ANTIGEN PEPTIDE TRANSPORTER 1; APT1;; RING4 preferredTitle TRANSPORTER, ATP-BINDING CASSETTE, MAJOR HISTOCOMPATIBILITY COMPLEX, 1; TAP1 textSectionList textSection textSectionTitle Description textSectionContent The ATP-binding cassette transporter TAP translocates peptides from the cytosol to awaiting major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum. TAP is made up of the TAP1 and TAP2 ({170261}) polypeptides. textSectionName description textSectionTitle Cloning textSectionContent A gene in the MHC with a role in antigen presentation was isolated by {15:Trowsdale et al. (1990)} and by {14:Spies et al. (1990)}. {14:Spies et al. (1990)} referred to the gene product as peptide supply factor (PSF). They identified the gene by deletion mapping in mutants and by chromosome walking. They pointed out that PSF is homologous to mammalian and bacterial ATP-dependent transport proteins, suggesting that it operates in the intracellular transport of peptides. {15:Trowsdale et al. (1990)} prepared probes from genomic clones from the MHC region and probed these onto cDNA libraries. Attention was focused on probes from regions of genomic DNA containing clusters of restriction sites with CpG dinucleotides in their recognition sequence, as these are often found near the 5-prime end of genes. One gene so isolated, called by them RING4, appeared to have a role in antigen presentation. It was found to have a sequence related to the ABC (ATP-binding cassette) superfamily of transporters. This superfamily includes the human multidrug-resistance proteins ({171050}, {171060}), a series of transporters from bacteria, including the oligopeptide permease system, and the human cystic fibrosis gene product. {11:Monaco et al. (1990)} demonstrated that in the mouse the Ham1 and Ham2 genes are located in the class II region of the MHC and are functionally and structurally homologous to TAP1 and TAP2, respectively. textSectionName cloning textSectionTitle Gene Function textSectionContent {12:Neefjes et al. (1993)} defined the conditions by which the TAP1 and TAP2 heterodimer is involved in assembly of class I molecules and presentation of endogenous peptides derived from nuclear and cytosolic proteins to CD8(+) T cells. TAP1 and TAP2 polypeptides possess a nucleotide-binding domain (NBD). {9:Karttunen et al. (2001)} presented biochemical and functional evidence that the NBDs of TAP1 and TAP2 are nonequivalent. Photolabeling experiments with 8-azido-ATP demonstrated a cooperative interaction between the 2 NBDs that can be stimulated by peptide. The substitution of key lysine residues in the Walker A motifs of TAP1 and TAP2 suggested that TAP1-mediated ATP hydrolysis is not essential for peptide translocation but that TAP2-mediated ATP hydrolysis is critical, not only for translocation, but for peptide binding. By comparative sequence analysis, {13:Ritz et al. (2003)} predicted that glu263 or phe265 of TAP1 are critical for TAP transporter function. They found that deletion or mutation of phe265 of TAP1 had little effect on TAP function, whereas deletion or alteration of glu264 had a major effect. textSectionName geneFunction textSectionTitle Mapping textSectionContent The TAP1 gene maps to chromosome 6p21.3 within the MHC. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent The MHC encodes the class I and class II families of glycoproteins that present peptides for immunorecognition by cytotoxic and helper T lymphocytes, respectively. Class I molecules bind peptides generated by degradation of proteins intracellularly, whereas class II molecules associate mainly with peptides derived from endocytosed extracellular proteins. Two genes encode components of the proteasome complex (see {176842}), which degrades cytosolic proteins and may generate antigenic peptides. Two closely linked genes, PSF1 and PSF2, encode subunits of a transporter that presumably translocates peptides into an exocytic compartment where they associate with class I molecules. The location of these genes in the MHC in close linkage to the class I and class II gene families suggests that they coevolved to optimize functional interactions. If this is so, the question is raised whether the proteasome subunits and the transporter genes, like most class I and class II genes, are polymorphic. Both proteasome subunits display electrophoretic polymorphism in the mouse. Allelic variation in the peptide transporter might influence the selection of peptide epitopes presented by class I molecules. {3:Colonna et al. (1992)} investigated variability of PSF1 and PSF2 by SSCP analysis and DNA sequencing. They identified several variants and examined possible involvement of the PSF1 and PSF2 genes in susceptibility to MHC-associated diseases such as ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two diallelic variants were identified in the PSF1 gene and 3 in the PSF2 gene. {16:Van Endert et al. (1992)} noted that screening for novel genes within the class II region of the major histocompatibility complex led to discovery of 4 genes residing in a closely linked complex within a 50-kb region upstream of the HLA-DO gene ({142920}). The TAP1 (also known as RING4 or PSF1) and TAP2 (also known as RING11 or PSF2) genes belong to a family of membrane transporters that possess an ATP binding cassette and 6 to 8 transmembrane domains. The other 2 genes, LMP2 (also known as RING12; {177045}) and LMP7 (also known as RING10; {177046}), encode proteins that belong to a large multicatalytic cytosolic protease complex referred to as the proteasome, or large multifunctional protease (LMP). Studying DNA from 27 consanguineous human cell lines, {16:van Endert et al. (1992)} sought genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. Studies demonstrated strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appeared to be in linkage disequilibrium with HLA-DR (see HLA-DRA, {142860}) alleles and RFLPs in the HLA-DO gene. A high rate of recombination seemed to occur in the center of the complex, between the TAP1 and TAP2 genes. {1:Cerundolo et al. (1990)} described a mutant cell line that had lost a function required for presentation of intracellular viral antigens with class I molecules of the MHC, but retained the capacity to present defined epitopes as extracellular peptides. {1:Cerundolo et al. (1990)} demonstrated that the genetic defect mapped within the MHC region on human chromosome 6. They showed that the presence of a normal human chromosome 6 in a hybrid cell was necessary for the correction of the defect. The cell line with the defective function carried a large homozygous deletion on 6p between the DP-alpha-2 locus ({142880}) and the complement gene cluster. {1:Cerundolo et al. (1990)} demonstrated further that the genetic defect resulted also in defective expression of class I molecules at the cell surface. They interpreted this to mean that class I assembly and transport are facilitated by association with peptides derived from intracellular antigens. {5:DeMars et al. (1985)} had isolated mutants with derangement in class I antigen expression, after mutagenic treatment of human B lymphoblastoid cell lines. The mutant cells had simultaneously reduced expression of HLA-B antigens even though their genes and the B2M gene were present and transcribed. Antigen expression was fully restored in hybrids of these mutants with other B lymphoblastoid cells. Individuals with certain HLA-DR alleles have an increased relative risk of developing insulin-dependent diabetes mellitus (IDDM; {222100}). The disease association is even stronger with certain HLA-DQ (see HLA-DQA, {146880}) alleles, but there is little association with HLA-DP providing a boundary of disease association to the 430 kb between DQ and DP. The TAP genes map approximately midway between DP and DQ. Studying single-stranded conformational polymorphism at the TAP1 locus in diabetics and normal controls, {8:Jackson and Capra (1993)} determined relative risks. In a population group studied extensively previously, they found a higher association of a TAP1 allele with IDDM than with any single HLA-DP allele, but the risk was lower than with HLA-DQB1*0302 (see HLA-DQB1, {604305}). The data provided new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1. {2:Chen et al. (1996)} evaluated 79 human solid tumors and cell lines for genetic abnormalities in TAP1 that might have led to an acquired loss of antigen presenting ability. They discovered a mutation (R659Q; {170260.0003}) in the TAP1 gene near the ATP-binding site in a human small cell lung cancer cell line. This cell line was heterozygous for this allele, but only the R659Q allele was transcribed into RNA. Even though the R659Q protein was expressed, the cells acted as if they were TAP-deficient by peptide binding and antigen presentation studies. {2:Chen et al. (1996)} showed that transfection of a functional TAP1 allele into the cells corrected the deficiency phenotype. {4:Cullen et al. (1997)} noted that studies of linkage disequilibrium across the HLA class II region have been useful in predicting where recombination is most likely to occur. The strong associations between genes was in the 85-kb region from DQB1 to DRB1 ({142857}) are consistent with low frequency of recombination in this segment of DNA. Conversely, a lack of association between alleles of TAP1 and TAP2 (which are separated by approximately 15 kb) has been observed, suggesting that recombination occurs here with relatively high frequency. {4:Cullen et al. (1997)} confirmed the increased rate of recombination in this and other segments. They noted a (TGGA)12 tandem repeat within the TAP2 gene possibly associated with the increased rate of recombination. In a Japanese woman with type I bare lymphocyte syndrome, {6:Furukawa et al. (1999)} identified homozygosity for a splice site mutation in intron 1 of the TAP1 gene ({170260.0004}). textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent Class I MHC molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. {7:Huh et al. (2000)} showed that in mice genetically deficient for cell surface class I MHC, due to deletion of either TAP1 or beta-2-microglobulin ({109700}), or for a class I MHC receptor component, CD3-zeta ({186780}), refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation is enhanced, and long-term depression is absent. Specific class I MHC mRNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrated an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system. textSectionName animalModel geneMapExists true editHistory alopez : 05/25/2012 mgross : 1/11/2006 carol : 7/15/2005 terry : 7/13/2005 carol : 8/17/2001 mcapotos : 8/17/2001 mcapotos : 8/16/2001 mcapotos : 8/6/2001 terry : 8/1/2001 carol : 5/25/2001 carol : 1/5/2001 alopez : 12/3/1999 carol : 11/9/1999 psherman : 9/22/1999 psherman : 6/24/1998 jenny : 4/8/1997 terry : 4/4/1997 mark : 5/31/1996 terry : 5/29/1996 terry : 7/15/1994 davew : 7/14/1994 warfield : 4/21/1994 carol : 12/13/1993 carol : 9/10/1993 carol : 2/3/1993 dateCreated Wed, 03 Jun 1992 03:00:00 EDT creationDate Victor A. McKusick : 6/3/1992 epochUpdated 1337929200 dateUpdated Fri, 25 May 2012 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1038/345449a0 publisherName Nature Publishing Group title Presentation of viral antigen controlled by a gene in the major histocompatibility complex. mimNumber 170260 referenceNumber 1 publisherAbbreviation NPG pubmedID 2342577 source Nature 345: 449-452, 1990. authors Cerundolo, V., Alexander, J., Anderson, K., Lamb, C., Cresswell, P., McMichael, A., Gotch, F., Townsend, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0696-210 publisherName Nature Publishing Group title A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. mimNumber 170260 referenceNumber 2 publisherAbbreviation NPG pubmedID 8640228 source Nature Genet. 13: 210-213, 1996. authors Chen, H. L., Gabrilovich, D., Tampe, R., Girgis, K. R., Nadaf, S., Carbone, D. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1570316 publisherName HighWire Press title Allelic variants of the human putative peptide transporter involved in antigen processing. mimNumber 170260 referenceNumber 3 publisherAbbreviation HighWire pubmedID 1570316 source Proc. Nat. Acad. Sci. 89: 3932-3936, 1992. authors Colonna, M., Bresnahan, M., Bahram, S., Strominger, J. L., Spies, T. pubmedImages false publisherUrl http://highwire.stanford.edu title Characterization of recombination in the HLA class II region. mimNumber 170260 referenceNumber 4 pubmedID 9012413 source Am. J. Hum. Genet. 60: 397-407, 1997. authors Cullen, M., Noble, J., Erlich, H., Thorpe, K., Beck, S., Klitz, W., Trowsdale, J., Carrington, M. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=3906658 publisherName HighWire Press title Mutations that impair a posttranscriptional step in expression of HLA-A and -B antigens. mimNumber 170260 referenceNumber 5 publisherAbbreviation HighWire pubmedID 3906658 source Proc. Nat. Acad. Sci. 82: 8183-8187, 1985. authors DeMars, R., Rudersdorf, R., Chang, C., Petersen, J., Strandtmann, J., Korn, N., Sidwell, B., Orr, H. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI5335 publisherName Journal of Clinical Investigation title Splice acceptor site mutation of the transporter associated with antigen processing-1 gene in human bare lymphocyte syndrome. mimNumber 170260 referenceNumber 6 publisherAbbreviation JCI pubmedID 10074494 source J. Clin. Invest. 103: 755-758, 1999. authors Furukawa, H., Murata, S., Yabe, T., Shimbara, N., Keicho, N., Kashiwase, K., Watanabe, K., Ishikawa, Y., Akaza, T., Tadokoro, K., Tohma, S., Inoue, T., Tokunaga, K., Yamamoto, K., Tanaka, K., Juji, T. pubmedImages true publisherUrl http://www.jci.org articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11118151 publisherName HighWire Press title Functional requirement for class I MHC in CNS development and plasticity. mimNumber 170260 referenceNumber 7 publisherAbbreviation HighWire pubmedID 11118151 source Science 290: 2155-2159, 2000. authors Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., Shatz, C. J. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8248212 publisherName HighWire Press title TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility. mimNumber 170260 referenceNumber 8 publisherAbbreviation HighWire pubmedID 8248212 source Proc. Nat. Acad. Sci. 90: 11079-11083, 1993. authors Jackson, D. G., Capra, J. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11381133 publisherName HighWire Press title Distinct functions and cooperative interaction of the subunits of the transporter associated with antigen processing (TAP). mimNumber 170260 referenceNumber 9 publisherAbbreviation HighWire pubmedID 11381133 source Proc. Nat. Acad. Sci. 98: 7431-7436, 2001. authors Karttunen, J. T., Lehner, P. J., Gupta, S. S., Hewitt, E. W., Cresswell, P. pubmedImages true publisherUrl http://highwire.stanford.edu title Defective expression of HLA class I antigens: a case of the bare lymphocyte without immunodeficiency. mimNumber 170260 referenceNumber 10 pubmedID 3891604 source Immunogenetics 21: 549-558, 1985. authors Maeda, H., Hirata, R., Chen, R. F., Suzaki, H., Kudoh, S., Tohyama, H. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=2270487 publisherName HighWire Press title Transport protein genes in the murine MHC: possible implications for antigen processing. mimNumber 170260 referenceNumber 11 publisherAbbreviation HighWire pubmedID 2270487 source Science 250: 1723-1726, 1990. authors Monaco, J. J., Cho, S., Attaya, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8342042 publisherName HighWire Press title Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. mimNumber 170260 referenceNumber 12 publisherAbbreviation HighWire pubmedID 8342042 source Science 261: 769-771, 1993. Note: Erratum: Science 264: 16 only, 1994. authors Neefjes, J. J., Momburg, F., Hammerling, G. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=12517960 publisherName HighWire Press title Impaired transporter associated with antigen processing (TAP) function attributable to a single amino acid alteration in the peptide TAP subunit TAP1. mimNumber 170260 referenceNumber 13 publisherAbbreviation HighWire pubmedID 12517960 source J. Immun. 170: 941-946, 2003. authors Ritz, U., Drexler, I., Sutter, D., Abele, R., Huber, C., Seliger, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/348744a0 publisherName Nature Publishing Group title A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. mimNumber 170260 referenceNumber 14 publisherAbbreviation NPG pubmedID 2259384 source Nature 348: 744-747, 1990. authors Spies, T., Bresnahan, M., Bahram, S., Arnold, D., Blanck, G., Mellins, E., Pious, D., DeMars, R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/348741a0 publisherName Nature Publishing Group title Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. mimNumber 170260 referenceNumber 15 publisherAbbreviation NPG pubmedID 2259383 source Nature 348: 741-744, 1990. authors Trowsdale, J., Hanson, I., Mockridge, I., Beck, S., Townsend, A., Kelly, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1360671 publisherName HighWire Press title Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes. mimNumber 170260 referenceNumber 16 publisherAbbreviation HighWire pubmedID 1360671 source Proc. Nat. Acad. Sci. 89: 11594-11597, 1992. authors van Endert, P. M., Lopez, M. T., Patel, S. D., Monaco, J. J., McDevitt, H. O. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:98483 mgiHumanDisease false ncbiReferenceSequences 530429020,530429663,530382459,530428442,530428103,530427830,530428742,530429363,53759115 refSeqAccessionIDs NG_011759.1 dermAtlas false hprdIDs 01359 swissProtIDs Q03518 zfinIDs ZDB-GENE-050517-43 uniGenes Hs.352018 gtr true cmgGene false ensemblIDs ENSG00000168394,ENST00000354258 umlsIDs C1336575 genbankNucleotideSequences 45439863,71516736,34526925,19068326,1054740,3551230,34367172,221044005,34634,3551228,24430271,34529054,52421005,431326,511815256,431324,431325,45379240,431322,36060,431323,123999611,546537,546538,54114714,546540,546541,32968209,546542,45181462,164695545,463918,37962921,1200313,38001,157929181,146090563,463920,148154031,58696580,20136397,33878458,18857824 geneTests true approvedGeneSymbols TAP1 geneIDs 6890 proteinSequences 3036972,3036970,930122,3036971,3036968,3036969,3551231,1054745,221044006,3551229,34636,119624051,119624053,119624052,119624055,119624054,119624057,123999612,119624056,635372931,36061,45181463,1200314,463919,45181465,37962922,189053993,15559426,215273957,9665248,463921,157929182,4261755,4261754,20136398,4261756 nextGxDx false locusSpecificDBs http://structure.bmc.lu.se/idbase/TAP1base/;;TAP1base: Mutation registry for TAP1 deficiency;;;http://www.ebi.ac.uk/imgt/hla/;;IMGT/HLA Database

entryList

entry status live allelicVariantExists true epochCreated 990514800 geneMap geneSymbols NOD2, CARD15, IBD1, CD, ACUG, PSORAS1 sequenceID 11126 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 605956 phenotypeInheritance Autosomal dominant phenotype Blau syndrome phenotypeMimNumber 186580 phenotypeMappingKey 3 mimNumber 605956 phenotypeInheritance None phenotype Sarcoidosis, early-onset phenotypeMimNumber 609464 phenotypeMimNumber 266600 mimNumber 605956 phenotypeInheritance Multifactorial phenotypicSeriesMimNumber 266600 phenotypeMappingKey 3 phenotype {Inflammatory bowel disease 1} phenotypeMappingKey 3 mimNumber 605956 phenotypeInheritance None phenotype {Psoriatic arthritis, susceptibility to} phenotypeMimNumber 607507 chromosomeLocationStart 50727506 chromosomeSort 343 chromosomeSymbol 16 mimNumber 605956 geneInheritance None confidence C mappingMethod REc, Fd geneName Nucleotide-binding oligomerization domain protein 2 mouseMgiID MGI:2429397 mouseGeneSymbol Nod2 computedCytoLocation 16q12.1 cytoLocation 16q12 transcript uc002egm.1 chromosomeLocationEnd 50766989 chromosome 16 contributors Paul J. Converse - updated : 9/22/2014 Ada Hamosh - updated : 6/2/2014 Ada Hamosh - updated : 7/23/2012 Ada Hamosh - updated : 2/27/2012 Paul J. Converse - updated : 8/5/2011 Paul J. Converse - updated : 9/28/2010 Paul J. Converse - updated : 2/4/2010 Paul J. Converse - updated : 1/7/2010 Cassandra L. Kniffin - updated : 6/2/2009 Cassandra L. Kniffin - updated : 11/30/2007 Patricia A. Hartz - updated : 10/31/2007 Ada Hamosh - updated : 7/24/2007 Victor A. McKusick - updated : 5/31/2007 George E. Tiller - updated : 1/16/2007 Marla J. F. O'Neill - updated : 5/24/2006 Victor A. McKusick - updated : 1/20/2006 Paul J. Converse - updated : 10/27/2005 Marla J. F. O'Neill - updated : 9/1/2005 Cassandra L. Kniffin - updated : 7/11/2005 Victor A. McKusick - updated : 3/21/2005 Victor A. McKusick - updated : 3/15/2005 Ada Hamosh - updated : 2/25/2005 Marla J. F. O'Neill - updated : 5/3/2004 George E. Tiller - updated : 4/28/2004 Victor A. McKusick - updated : 4/27/2004 Victor A. McKusick - updated : 4/21/2004 Marla J. F. O'Neill - updated : 4/2/2004 Victor A. McKusick - updated : 10/8/2003 Victor A. McKusick - updated : 9/5/2003 Victor A. McKusick - updated : 5/2/2003 Victor A. McKusick - updated : 4/25/2003 Victor A. McKusick - updated : 3/3/2003 Victor A. McKusick - updated : 2/26/2003 Victor A. McKusick - updated : 10/1/2002 Victor A. McKusick - updated : 9/24/2002 Victor A. McKusick - updated : 9/12/2002 Victor A. McKusick - updated : 7/17/2002 Victor A. McKusick - updated : 6/26/2002 Victor A. McKusick - updated : 4/12/2002 Victor A. McKusick - updated : 3/1/2002 Victor A. McKusick - updated : 8/23/2001 Ada Hamosh - updated : 5/22/2001 clinicalSynopsisExists false mimNumber 605956 allelicVariantList allelicVariant status live name INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO text {34:Ogura et al. (2001)} sequenced all coding exons and flanking introns of the NOD2 gene in 12 affected individuals from pure Crohn disease (IBD1; {266600}) families with increased linkage scores at D16S3396, which is tightly linked to NOD2, as well as in 4 case controls. In 3 Crohn disease patients, they identified a 1-bp insertion (C) at nucleotide 3020 (3020insC) in exon 11 of the NOD2 gene, resulting in a frameshift at the second nucleotide of codon 1007 and a leu1007-to-pro substitution in the tenth LRR, followed by a premature stop codon. The predicted truncated NOD2 protein contained 1,007 amino acids instead of the 1,040 amino acids of the wildtype protein. {34:Ogura et al. (2001)} observed preferential transmission from heterozygous parents to affected children of the 3020insC mutation (P of 0.0046). There was no preferential transmission of this mutation in families with ulcerative colitis. The frequency of the 3020insC mutation was 8.4% among Jewish Caucasians and 8.1% among non-Jewish Caucasians. The frequency among control Caucasians was 4.0%. The allele frequency of this mutation from 182 unrelated ulcerative colitis patients was 3.0%. The genotype frequencies of the 3020insC mutation in unrelated Crohn disease individuals was 11 homozygotes, 46 heterozygotes, and 359 wildtype homozygotes. The genotype-relative risk for heterozygous and homozygous 3020insC was 1.5 and 17.6, respectively, as compared with wildtype controls. Lipopolysaccharide (LPS) from various bacteria induced nuclear factor kappa-B (NFKB; see {164011}) activation in cells expressing wildtype NOD2, but not in cells transfected with control plasmid. Cells transfected with NOD2 carrying the 3020insC mutation had greatly diminished response to LPS, with the most significant reduction in response to Salmonella, Shigella, Klebsiella, Campylobacter, and Neisseria gonorrhea. {16:Hugot et al. (2001)} independently identified this mutation in association with Crohn disease; however, because they used the 1,013-amino acid NOD2B sequence, they reported the mutation as a frameshift at codon 980. {13:Hampe et al. (2001)} studied the association between this mutation and inflammatory bowel disease in 512 affected individuals from 309 German or British families, 369 German trios (patients with sporadic inflammatory bowel disease and their unaffected parents), and 272 normal controls. Family-based association analyses were consistently positive in 95 British and 99 German affected sib pairs with Crohn disease; the association was confirmed in 304 German trios with Crohn disease. No association was seen in the 115 sib pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 and 42.1, respectively. A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn disease. To test the association of CARD15 with intestinal permeability, {2:Buhner et al. (2006)} studied 128 patients with quiescent CD, 129 first-degree relatives, 66 nonrelated household members, and 96 healthy controls. There were 3 main findings. Healthy first-degree relatives of patients with CD showed increased permeability in contrast with unrelated household members and controls. Secondly, the prevalence of the CARD15 3020insC mutation was similar in first-degree relatives and CD patients and higher compared with controls. Thirdly, in healthy first-degree relatives, high mucosal permeability and the presence of a CARD15 3020insC mutation were significantly associated. mutations NOD2, 1-BP INS, 3020C number 1 clinvarAccessions RCV000004955;;1 status live name INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO dbSnps rs2066845 text {16:Hugot et al. (2001)} identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene that was associated with an increased susceptibility to Crohn disease (IBD1; {266600}). The allele frequency of this mutation was 0.11 among Crohn disease patients, 0.03 among ulcerative colitis (IBD1; {266600}) patients, and 0.04 among unaffected controls. This mutation was designated GLY908ARG in the study of {47:Vermeire et al. (2002)}. mutations NOD2, GLY908ARG number 2 clinvarAccessions RCV000004956;;1 status live name INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO dbSnps rs2066844 text {16:Hugot et al. (2001)} identified a mutation leading to an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene that was associated with increased susceptibility to Crohn disease (IBD1; {266600}). The allele frequency of this mutation was 0.06 among Crohn disease patients, 0.01 among unaffected controls, and it was not present among ulcerative colitis patients. This mutation was designated ARG702TRP in the study of {47:Vermeire et al. (2002)}. mutations NOD2, ARG702TRP number 3 clinvarAccessions RCV000004957;;1 status live name BLAU SYNDROME dbSnps rs104895461 text In affected members of 2 families with Blau syndrome ({186580}), {29:Miceli-Richard et al. (2001)} found a 1001G-A transition in the NOD2 gene, resulting in an arg334-to-gln (R334Q) amino acid change. mutations NOD2, ARG334GLN number 4 clinvarAccessions RCV000004958;;1;;;RCV000084070;;0 status live name BLAU SYNDROME dbSnps rs104895460 text In a proband and his father with Blau syndrome ({186580}), {29:Miceli-Richard et al. (2001)} found a 1405C-T transition in the NOD2 gene, resulting in a leu469-to-phe (L469F) amino acid change. mutations NOD2, LEU469PHE number 5 clinvarAccessions RCV000004959;;1;;;RCV000084086;;0 status live name BLAU SYNDROME dbSnps rs104895462 text In affected members of a family with Blau syndrome ({186580}), {29:Miceli-Richard et al. (2001)} found a 1000C-T transition in the NOD2 gene, resulting in an arg334-to-trp (R334W) amino acid change. In a study of 10 early-onset sarcoidosis ({609464}) cases in Japan, {18:Kanazawa et al. (2005)} found that 4 had the 1000C-T transition (R334W) in the CARD15 gene. {6:Dhondt et al. (2008)} identified heterozygosity for the R334W mutation in a patient with Blau syndrome. The mutation occurred in the central nucleotide-binding oligomerization domain. mutations NOD2, ARG334TRP number 6 alternativeNames SARCOIDOSIS, EARLY-ONSET, INCLUDED clinvarAccessions RCV000004961;;1;;;RCV000004960;;1 status live name INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO dbSnps rs5743289 text In Jewish patients with Crohn disease (IBD1; {266600}), {41:Sugimura et al. (2003)} found a novel disease-predisposing variant, IVS8+158, which is a C-to-T mutation in the palindrome sequence in the intron 8 splicing region. mutations NOD2, IVS8+158 number 7 clinvarAccessions RCV000004962;;1 status live name SARCOIDOSIS, EARLY-ONSET dbSnps rs104895472 text Among 10 cases of early-onset sarcoidosis ({609464}) studied retrospectively in Japan, {18:Kanazawa et al. (2005)} found that 4 had different novel missense mutations in the CARD15 gene, one of which was a 1487A-T transversion resulting in a his496-to leu (H496L) substitution. mutations NOD2, HIS496LEU number 8 clinvarAccessions RCV000004963;;1 status live name SARCOIDOSIS, EARLY-ONSET dbSnps rs104895476 text Among 10 cases of early-onset sarcoidosis ({609464}) studied retrospectively in Japan, {18:Kanazawa et al. (2005)} found that 1 was compound heterozygous for 2 missense mutations in the CARD15 gene: a 1146C-G transversion resulting in an asp382-to-glu (D382E) substitution and a 1834G-A transition resulting in an ala612-to-thr (A612T) substitution ({605956.0010}). mutations NOD2, ASP382GLU number 9 clinvarAccessions RCV000004964;;1 status live name SARCOIDOSIS, EARLY-ONSET dbSnps rs104895438 text See {605956.0009} and {18:Kanazawa et al. (2005)}. mutations CARD15, ALA612THR number 10 clinvarAccessions RCV000004965;;1 status live name BLAU SYNDROME dbSnps rs104895477 text In a mother and daughter with Blau syndrome ({186580}), {43:van Duist et al. (2005)} identified a heterozygous 1147G-A transition in exon 4 of the CARD15 gene, resulting in a glu383-to-lys (E383K) substitution. The mutation is in a highly conserved region in the central nucleotide-binding NACHT domain and may result in increased signaling. mutations NOD2, GLU383LYS number 11 clinvarAccessions RCV000084076;;0;;;RCV000004966;;1 status live name INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO dbSnps rs2066847 text {26:MacArthur et al. (2012)} reported a single-basepair insertion of a cytosine between nucleotides 3016 and 3017 of the NOD2 gene, leading to a frameshift that was associated with Crohn disease (IBD1; {266600}), with a genomewide-significant imputed P value of 1.78 x 10(-14), just 2 orders of magnitude more significant than the best tag SNP. mutations NOD2, 1-BP INS, 3016C ({dbSNP rs2066847}) number 12 clinvarAccessions RCV000023505;;1 prefix * titles alternativeTitles CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 15; CARD15 preferredTitle NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2 textSectionList textSection textSectionTitle Description textSectionContent APAF1 ({602233}) and NOD1 ({605980}), also called CARD4, are members of a family of intracellular proteins that contain an N-terminal caspase recruitment domain (CARD), a centrally located nucleotide-binding domain (NBD), and a C-terminal regulatory domain. In the case of APAF1, the C-terminal regulatory domain consists of WD40 repeats, whereas NOD1 has leucine-rich repeats (LRRs). The APAF1 WD40 repeats act as recognition domains for mitochondrial damage, which leads to APAF1 oligomerization and eventual apoptosis. NOD1 also promotes apoptosis, but unlike APAF1, it does so through nuclear factor kappa-B (NFKB; see {164011}) activation. Also, NOD1 has striking structural similarity to a class of disease-resistance genes in plants that induce localized cell death at the site of pathogen invasion ({35:Ogura et al., 2001}). textSectionName description textSectionTitle Cloning textSectionContent By searching a genomic database for NOD1 homologs, followed by 5-prime RACE and RT-PCR, {35:Ogura et al. (2001)} obtained cDNAs encoding NOD2. Sequence analysis predicted that the 1,040-amino acid NOD2 protein, which is 34% identical to NOD1, contains 2 N-terminal CARDs fused to a central NBD domain followed by 10 tandem LRRs. {34:Ogura et al. (2001)} also identified a NOD2 variant encoding a 1,013-amino acid protein, which they called NOD2B. Northern blot analysis detected 7.0- and 5.5-kb NOD2 transcripts in peripheral blood leukocytes, with little or no expression found in other tissues. RT-PCR analysis revealed expression primarily in monocytes. In contrast, NOD1 and APAF1 are broadly expressed. Expression of NOD2 or NOD2B resulted in NFKB activation, and mutants lacking the LRRs had enhanced NFKB activation. The authors determined that both intact CARD domains are necessary and sufficient for IKK-gamma (IKBKG; {300248})- and RICK (RIPK2; {603455})-dependent NFKB activation. Coimmunoprecipitation analysis showed that the CARD domain of RICK interacts with the CARD domains of NOD2. By 5-prime RACE and semiquantitative RT-PCR, {20:King et al. (2007)} showed that most human NOD2 transcripts in blood leukocytes and colon are products of an alternative first exon. They concluded that the principal NOD2 protein product lacks 27 previously reported N-terminal amino acids. textSectionName cloning textSectionTitle Gene Structure textSectionContent {20:King et al. (2007)} identified an alternative first exon that lies within a strong CpG island about 3.5 kb upstream of the canonical first exon of the NOD2 gene. textSectionName geneStructure textSectionTitle Mapping textSectionContent By analysis of BAC clones, {35:Ogura et al. (2001)} determined that the NOD2 gene maps to 16q12 and contains 12 coding exons. textSectionName mapping textSectionTitle Gene Function textSectionContent {35:Ogura et al. (2001)} proposed that NOD2 serves as an intracellular receptor for bacterial products in monocytes and transduces signals leading to NFKB activation. {4:Cooney et al. (2010)} showed that activation of NOD2 with muramyldipeptide induced autophagy in dendritic cells (DCs) that required RIPK2, PI3K (see {601232}), ATG5 ({604261}), ATG7 ({608760}), and ATG16L1 ({610767}), but not NALP3 (NLRP3; {606416}). DCs from Crohn disease (CD; {266600}) patients with susceptibility variants in NOD2 (e.g., 1007fs; {605956.0001}) or ATG16L1 (T300A; {610767.0001}) were deficient in autophagy induction. DCs from CD patients with NOD2 variants also showed reduced localization of bacteria in autophagolysosomes, which could be reversed by treatment with rapamycin. {4:Cooney et al. (2010)} concluded that NOD2 influences bacterial degradation and interacts with the major histocompatibility complex class II antigen presentation machinery within DCs, and that ATG16L1 and NOD2 are linked within 1 functional pathway. {1:Brain et al. (2013)} detected upregulated expression of MIR29A ({610782}), MIR29B (see {610783}), and MIR29C ({610784}) in human DCs stimulated with NOD2. They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 (IL23A; {605580}) component indirectly, most likely through a reduction of the transcription factor ATF2 ({123811}). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. {1:Brain et al. (2013)} proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease. {32:Nakamura et al. (2014)} showed that 2 endolysosomal peptide transporters, SLC15A3 ({610408}) and SLC15A4 ({615806}), are preferentially expressed by dendritic cells, especially after Toll-like receptor (TLR) stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, {32:Nakamura et al. (2014)} concluded that dendritic cell endosomes are specialized platforms for both the luminal and cytosolic sensing of pathogens. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Susceptibility to Inflammatory Bowel Disease {34:Ogura et al. (2001)} and {16:Hugot et al. (2001)} identified mutations in the NOD2 gene (see, e.g., {605956.0001}-{605956.0003}) that were associated with susceptibility to Crohn disease (IBD1; {266600}). {24:Lesage et al. (2002)} reported mutation analysis of the CARD15 gene in 453 patients with Crohn disease, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (IBD1; {266600}), and 103 healthy control subjects. Although no mutations were found to be associated with ulcerative colitis, 50% of patients with Crohn disease carried at least 1 potential disease-causing mutation, including 17% who had a double mutation. There were 27 rare additional mutations. Each of 3 polymorphisms (R702W, {605956.0003}; G908R, {605956.0002}; and 1007fs, {605956.0001}) were confirmed to be intermittently associated with susceptibility to Crohn disease. These 3 main variants represented 32%, 18%, and 31%, respectively, of the total Crohn disease mutations, whereas the total of the 27 rare mutations represented 19% of disease-causing mutations. Altogether, 93% of the mutations were located in the distal third of the gene. These observations confirmed the gene-dosage effect in Crohn disease. Patients with double-dose mutations were characterized by a younger age at onset, a more frequent stricturing phenotype, and a less frequent colonic involvement than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of Crohn disease patients with or without mutation. Crohn disease exhibits a 2- to 4-fold increased frequency in Jews as compared with other ethnic/racial groups. {41:Sugimura et al. (2003)} sought additional NOD2 mutations in patients with CD, since the 3 coding variants that had been reported were found in only 30 to 40% of patients and could not account for all the linkage between CD and IBD1 locus ({266600}). They studied 64 Ashkenazi Jewish and 147 non-Jewish white families. After excluding the influence of the 3 independent disease-predisposing mutations (1007fs, G908R, and R702W), significant linkage of the IBD1 locus on chromosome 16 to Crohn disease was found in Jews, with 2 peaks at D16S403 (mean allele sharing (MAS) = 0.70) and D16S411 (MAS = 0.59). They observed an increased frequency of a haplotype carrying only the 268S variant in Jewish patients but not in non-Jews, suggesting the existence of a Jewish-specific additional disease-predisposing factor on this haplotype. Sequencing of this haplotype revealed a new variant: IVS8+158 (referred to as JW1; {605956.0007}). The 268S-JW1 combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for CD among reported disease-predisposing mutations in Jews. Thus, in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) existed on the 268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the higher risk for CD in Ashkenazi Jews as compared with non-Jews. Among 483 Japanese patients with Crohn disease, {50:Yamazaki et al. (2002)} tested for the 3 mutations found to be independent risk factors for Crohn disease in Caucasian patients (R702W, G908R, and 1007fs). None of these mutations was identified; only an R702Q substitution was found in a single patient. Direct sequencing of DNA from 96 of these patients in the regions containing the 3 reported major mutations detected no sequence alterations of consequence. {50:Yamazaki et al. (2002)} therefore concluded that NOD2/CARD15 is not a major contributor to Crohn disease susceptibility in the Japanese. By using assays based on NFKB activation, {3:Chamaillard et al. (2003)} showed that cytosolic CARD15 efficiently detects bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 variants that are associated with Crohn disease and 13 additional variants carried by Crohn disease patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable manifestations of Crohn disease. In contrast, CARD15 alleles associated with Blau syndrome ({186580}) promoted PGN-independent NFKB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites. {5:Croucher et al. (2003)} examined 23 SNPs in and around the CARD15 gene in large northern European and Korean samples of patients with CD and normal controls. In the European patients, they confirmed that the 3 disease-associated SNPs in CARD15 (R702W, G908R, and 1007fs) occur independently, but noted that they share a common background haplotype, suggesting a common origin and the possibility of an undiscovered, more strongly predisposing mutation. Korean CD patients have a phenotype identical to the European patients, but had not previously been screened for CARD15. The 3 disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. {5:Croucher et al. (2003)} concluded that the disease-associated mutations in Europeans, which are rare, arose after the Asian-European split. {44:Van Heel et al. (2003)} performed a genomewide scan of 137 Crohn disease affected relative pairs from 112 families. The authors verified linkage of Crohn disease to regions on chromosome 3 (IBD9; {608448}; p = 0.0009) and X (p = 0.001) in their cohort. Linkage to chromosome 16 (IBD1; {266600}) was observed in Crohn disease pairs not possessing common CARD15 mutations (p = 0.0007), 25 cM q telomeric of CARD15. Evidence for linkage to chromosome 19 (IBD6; {606674}) was observed in Crohn disease pairs not possessing CARD15 mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the IBD5 ({606348}) risk haplotype (p = 0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrated the complex genetic basis to Crohn disease, and that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex diseases. {40:Stoll et al. (2004)} identified variants in the DLG5 gene ({604090}) associated with inflammatory bowel disease. One of the risk-associated DLG5 haplotypes was distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism (SNP) 113G-A, resulting in the amino acid substitution arg30-to-gln (R30Q) in the DUF622 domain of DLG5 ({604090.0001}). The mutation was predicted to impede scaffolding of DLG5. They stratified the study sample according to the presence of risk-associated variants of CARD15 (1007fs, also known as 3020insC, {605956.0001}; G908R, {605956.0002}; R702W, {605956.0003}) to study potential gene-gene interaction. They found a significant difference in association of the 113A variant of DLG5 with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This suggested a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. {25:Li et al. (2004)} defined cytokine regulation in mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. MDP induced a broad array of transcripts, including interleukin-1-beta (IL1B; {147720}) and interleukin-8 (IL8; {146930}). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Modest induction of IL8 protein was observed in G908R and R702W homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. With MDP plus TNF-alpha (TNFA; {191160}), there was a synergistic induction of IL1B secretion. In leu1007fsinsC homozygotes, there was a profound defect in IL1B secretion despite marked induction of IL1B mRNA. {25:Li et al. (2004)} concluded that there is posttranscriptional dependency on the CARD15 pathway for IL1B secretion with MDP and TNF-alpha treatment and suggested that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients. {45:Van Heel et al. (2005)} analyzed the cytokine response of peripheral blood mononuclear cells to MDP. MDP induced strong IL8 secretion and substantially upregulated the secretion of TNF-alpha and IL1B induced by Toll-like receptor (see {601194}) ligands. At low nanomolar MDP concentrations, these effects were abolished by the most common Crohn disease NOD2/CARD15 double-mutant genotypes (702W/1007fs, 702W/702W, 1007fs/1007fs, and 908R/1007fs). {45:Van Heel et al. (2005)} suggested that NOD2 activation provides a priming signal to condition a broad early immune response to pathogens, and that the absence of this priming signal in NOD2-associated CD causes failure of early immune pathogen clearance and explains the abnormal adaptive immune responses to microbial antigens in CD patients. {33:Netea et al. (2005)} investigated the responses of mononuclear cells from Crohn disease patients to MDP and other muramyl peptides and found that patients homozygous for the NOD2fs mutation were totally unresponsive to a diaminopimelic acid-containing muramyl tripeptide, the specific agonist for NOD1, and to gram-negative bacterial peptidoglycan. In contrast, a Crohn disease patient with the R702W mutation had normal responses to peptidoglycan. RT-PCR analysis indicated that patients with Nod2fs expressed significantly higher levels of peptidoglycan recognition protein S (PGLYRP1; {604963}), which may have contributed to the downregulation of NOD1-dependent responses. {33:Netea et al. (2005)} concluded that there is unexpected cross-talk between the NOD1 and NOD2 signaling pathways and proposed that NOD1 functional defects may participate in the development of Crohn disease. In summarizing previous findings, {21:King et al. (2006)} stated that 3 common mutations in the CARD15 gene are associated with susceptibility to CD, and genetic data suggested a gene dosage model with an increased risk of 2- to 4-fold in heterozygotes and 20- to 40-fold in homozygotes. However, the discovery of numerous rare variants of CARD15 indicated that some heterozygotes with the common mutation have a rare mutation on the other CARD15 allele, which would support a recessive model for CD. {21:King et al. (2006)} screened CARD15 for mutations in 100 CD patients who were heterozygous for 1 of those 3 common mutations. They developed a strategy for evaluating potential disease susceptibility alleles that involved assessing the degree of evolutionary conservation of involved residues, predicted effects on protein structure and function, and genotyping in a large sample of cases and controls. The evolutionary analysis was aided by sequencing the entire coding region of CARD15 in 3 primates (chimp, gibbon, and tamarin) and aligning the human sequence with these and orthologs from other species. They found that 11 of the 100 CD patients screened had a second potential pathogenic mutation within the exonic and periexonic sequences examined. Assuming that there are no additional pathogenic mutations in noncoding regions, the study of {21:King et al. (2006)} suggested that most carriers of the common disease susceptibility alleles are true heterozygotes, and supported evidence for a gene dosage model. Four novel nonsynonymous mutations were detected. {28:Medici et al. (2006)} studied 23 CARD15 SNPs in a Norwegian population of 476 unrelated IBD patients and 236 controls in comparison to a well-studied German population of IBD patients and controls. They found significantly lower frequencies of the predisposing CARD15 SNPs (1007fs, G908R, and R702W) and no significant associations with CD in the Norwegian samples. The population-attributable risk percentage of the 3 CARD15 variants in the Norwegian cohort was one of the lowest reported for a European population (1.88%). {28:Medici et al. (2006)} stated that these results are consistent with a low frequency of the CARD15 variants in the northern European countries where the prevalence of IBD is greatest. {26:MacArthur et al. (2012)} performed a systematic survey of loss-of-function variants in human protein-coding genes from the 1000 Genomes Study and imputed 417 loss-of-function single-nucleotide variants and indels into a total of 13,241 patients representing 7 complex diseases, such as Crohn disease and rheumatory arthritis, along with 2,938 shared controls, who had previously been subjected to genomewide SNP genotyping (45:{49:Wellcome Trust Case Control Consortium, 2007}). {26:MacArthur et al. (2012)} confirmed a previously known frameshift indel in the NOD2 gene ({dbSNP rs2066847}, {605956.0012}) associated with Crohn disease with a genomewide-significant imputed P value of 1.78 x 10(-14) (2 orders of magnitude more significant than the best tag SNP). However, no other loss-of-function variants achieved genomewide significance, suggesting that common gene-disrupting variants play a minor role in complex disease predisposition. {39:Rivas et al. (2011)} used pooled next-generation sequencing to study 56 genes from regions associated with Crohn disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in 9 independent case-control series (16,054 Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy controls), they identified 4 additional independent risk factors in NOD2: R311W, S431L, R703C, and N852S. N852S occurred only in Ashkenazi Jewish individuals. Blau Syndrome and Early-Onset Sarcoidosis Blau syndrome ({186580}) is a rare autosomal dominant disorder characterized by early-onset granulomatous arthritis, uveitis, and skin rash with camptodactyly. In affected members of 4 families with Blau syndrome, {29:Miceli-Richard et al. (2001)} identified 3 different heterozygous mutations in the CARD15 gene (R334Q; {605956.0004}, L469F; {605956.0005}, and R334W; {605956.0006}). All mutations were located in the region encoding the nucleotide binding domain of CARD15; mutations identified patients with Crohn disease were located in the leucine-rich repeat domain of CARD15. Because Blau syndrome shows phenotypic overlap with early-onset sarcoidosis (EOS; {609464}), {29:Miceli-Richard et al. (2001)} also screened 2 patients with EOS for mutations in the CARD15 gene, but found none. However, {17:Kanazawa et al. (2004)} described a sporadic case of systemic granulomatosis syndrome with clinical features of EOS that showed one of the same CARD15 mutations ({605956.0007}) as detected in BS. {18:Kanazawa et al. (2005)} collected Japanese EOS cases retrospectively and searched for CARD15 mutations. Among 10 such cases, heterozygous missense mutations were found in 9; 4 showed an arg334-to-trp mutation ({605956.0006}) that had been reported in BS, 4 showed novel missense mutations, and 1 showed compound heterozygosity for 2 different missense mutations. All 6 of these variants of CARD15 showed increased basal NFKB activity. {18:Kanazawa et al. (2005)} concluded that the majority of early-onset sarcoidosis and Blau syndrome cases share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation. {12:Goyal et al. (2007)} reported an unusual case of a 12-year-old girl who presented with persistent focal seizures and MRI signal abnormalities. Brain biopsies showed marked dural granulomatous inflammation with focal extension into the brain parenchyma. Studies for systemic sarcoidosis were negative. Treatment with infliximab, a TNF-alpha inhibitor, resulted in clinical improvement. Family history revealed a paternal uncle and grandfather with Crohn disease, and molecular analysis identified 3 missense mutations in the NOD2 gene in the proband. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent {14:Hampe et al. (2002)} investigated the relationship between specific NOD2 genotypes and phenotypic characteristics of patients with Crohn disease. Hypotheses were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p less than 0.100) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohn disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8 (R702W), SNP12 (G908R), and SNP13 (1007fs). In the retrospective cohort, 6 clinical characteristics showed noteworthy haplotype association: fistulizing, disease of the ileum and left and right colon, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal disease (p = 0.006) and right colonic disease (p less than 0.001). A similar trend was noted in the Norwegian patients. {47:Vermeire et al. (2002)} collected a cohort of 231 patients with Crohn disease and 71 healthy control individuals from the Canadian province of Quebec to determine the prevalence of 3 sequence variants: leu1007fsinsC ({605956.0001}), gly908 to arg (G908R; {605956.0002}), and arg702 to trp (R702W; {605956.0003}). In this cohort, 45.0% of patients with Crohn disease carried at least 1 variant in the CARD15 gene, compared with 9.0% of control individuals. Allele frequencies of R702W, G908R, and leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with Crohn disease, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Analysis of the relationship between genotype and phenotype convincingly demonstrated that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P less than 0.001). Moreover, {47:Vermeire et al. (2002)} determined the haplotype structure surrounding this disease gene by genotyping 45 SNPs in the 177-kb region that contains the CARD15 gene. The structure helped clarify the history of these causal mutations. Their analysis showed that CARD15 involvement with Crohn disease is detectable by use of publicly available SNPs alone. {30:Murillo et al. (2002)} studied 130 Dutch patients with Crohn disease, with a median follow-up of 9.2 years, and 152 ethnically matched healthy controls. They confirmed reports that the CARD15 3020insC mutation increases susceptibility to Crohn disease, but could not confirm the relationship for the CARD15 low frequency G2722C missense mutation reported by {34:Ogura et al. (2001)}. {46:Van Heel et al. (2002)} discussed difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits. They used 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 sib pairs affected with Crohn disease and in a simplex family cohort. No evidence of linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 Crohn disease trios (2 parents and affected offspring) for the NOD2 variants R702W and leu1007fsinsC. {8:Fidder et al. (2003)} studied the frequency of 2 missense and 1 frameshift variant of CARD15 in Israeli Jewish Crohn disease and ulcerative colitis patients. The 2 missense mutations were R675W ({605956.0003}) and G881R ({605956.0002}); the frameshift mutation was 980FS981X ({605956.0001}). Mutations in CARD15 were observed with significantly greater frequency in Crohn disease patients (46/170, 27%) than in ulcerative colitis patients (7/68, 10%) (p = 0.005). Homozygosity and compound heterozygosity was found only in 7 (4%) patients with Crohn disease as compared to none of the ulcerative colitis patients. Similar rates were observed in Ashkenazi and non-Ashkenazi Jewish patients. Age of onset of disease was lower in Ashkenazi mutation carriers as compared to noncarriers of Ashkenazi origin (18.7 vs 25.8 years, respectively). No other phenotypic characteristics could distinguish mutation carriers from noncarriers. {19:Karason et al. (2003)} performed a genomewide linkage scan in psoriatic arthritis in a group of 178 patients from 39 Icelandic families and found a lod score of 2.17 on 16q ({607507}). Further analysis, conditional on paternal transmission to affected individuals, resulted in a lod score of 4.19. The peak of this lod score was within 20 Mb of the CARD15 gene. The region overlapping CARD15 had been implicated by a genomewide scan in psoriasis by {31:Nair et al. (1997)}. The possibility of a common susceptibility gene shared by psoriasis/psoriatic arthritis and Crohn disease was further supported by epidemiologic studies that noted an increased incidence of psoriasis and psoriatic arthritis in subjects with Crohn disease ({23:Lee et al., 1990}). See psoriasis susceptibility-1 (PSORS1; {177900}). In Newfoundland, {38:Rahman et al. (2003)} screened 187 patients with psoriatic arthritis and 136 healthy controls for the 3 common, independent sequence variants of CARD15: R702W ({605956.0003}), leu1007fsinsC ({605956.0001}), and G908R ({605956.0002}). In total, 53 of 187 (28.3%) probands with psoriatic arthritis had at least 1 variant of the CARD15 gene, compared with 16 of 136 (11.8%) controls; odds ratio = 2.97, p = 0.0005. Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with psoriatic arthritis, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to psoriatic arthritis independent of HLA-Cw*0602 (see HLA-C, {142840}), which of the HLA types shows the strongest association with psoriasis ({11:Gladman, 2002}). {38:Rahman et al. (2003)} stated that CARD15 was the first candidate gene identified in psoriatic arthritis that resides outside the major histocompatibility complex. They referred to CARD15 as a pleiotropic autoimmune gene, since it confers susceptibility to Crohn disease, Blau syndrome, and psoriatic arthritis. To determine whether CARD15 mutations account for the higher prevalence of Crohn disease in Ashkenazi Jews, {42:Tukel et al. (2004)} assessed the haplotypes and allele frequencies of the common mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls. A higher frequency of CARD15 mutations was found in Ashkenazi Jewish patients from multiplex families with CD from central (44%) versus eastern (24%) Europe, especially for the G908R and 1007fs mutations, and in Sephardi/Oriental Jewish patients (34.5%) compared with Ashkenazi (10.1%) or Sephardi/Oriental (5.4%) Jewish controls. {10:Giachino et al. (2004)} analyzed the 3 recurrent CARD15 variants (R702W, G908R, and 1007fs) in 184 CD and 92 UC Italian patients and in 177 healthy controls. They found significant associations for G908R and L1007fs with CD only. Analysis of mutation-phenotype correlations revealed an increased chance of mutation positivity in patients with strictures (OR, 2.76; 95% CI, 1.2-6.3) and fistulas (OR, 2.59; 95% CI 1.0-6.6), and a weaker association with ileal location of disease (OR, 3.03; 95% CI, 0.9-9.8). {10:Giachino et al. (2004)} concluded that the CARD15 genotype can serve as an explanatory variable for predicting the pattern of IBD presentation and progression. {18:Kanazawa et al. (2005)} retrospectively collected Japanese early-onset sarcoidosis (EOS; {609464}) cases in search of CARD15 mutations. Among 10 EOS cases, missense mutations were found in 9: 4 showed the R334W mutation ({605956.0006}) that had been reported in Blau syndrome; 4 showed different novel missense mutations; and 1 patient showed compound heterozygosity for 2 missense mutations ({605956.0009}-{605956.0010}). All 6 of these variants of CARD15 showed increased basal NFKB activity. {18:Kanazawa et al. (2005)} concluded that most EOS and Blau syndrome cases share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation. The {49:Wellcome Trust Case Control Consortium (2007)} described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. This analysis identified 9 associations with Crohn disease including CARD15, which was represented by {dbSNP rs17221417} (p = 9.4 x 10(-12)). textSectionName genotypePhenotypeCorrelations textSectionTitle Evolution textSectionContent Analysis of the evolution of CARD15 revealed strong conservation of the encoded protein, with identity to the human sequence ranging from 99.1% in the chimp to 44.5% in fugu ({21:King et al., 2006}). textSectionName evolution textSectionTitle Animal Model textSectionContent The mouse Nod2 locus is situated on chromosome 8 and comprises 12 exons, 11 of which encode the Nod2 protein. {36:Ogura et al. (2003)} performed sequence analysis of the mouse Nod2 gene from 45 different strains and identified extensive polymorphisms involving all exons of the gene. Studies of the polymorphisms demonstrated a conserved role for Nod2 in the response to bacterial components and suggested that selective evolutionary pressure exerted by pathogens may have contributed to the high level of variability of Nod2 sequences in both humans and mice. {37:Pauleau and Murray (2003)} generated mice lacking Nod2. Nod2 -/- mice were indistinguishable from wildtype mice and manifested no symptoms or pathology consistent with human Crohn disease. Macrophages of Nod2 -/- mice had nearly normal responses to TLR stimulation and to Ifng ({147570}) and Il10 ({124092}), which activate and deactivate macrophages, respectively. However, Nod2 -/- weanling mice better survived a lethal lipopolysaccharide (LPS) challenge than did wildtype weanling mice. {22:Kobayashi et al. (2005)} generated mice deficient in Nod2 by targeted disruption. Nod2-null mice were outwardly healthy and displayed normal lymphoid and myeloid cellular composition in the thymus and spleen. The mice also displayed no overt symptoms of intestinal inflammation when observed for up to 6 months. {22:Kobayashi et al. (2005)} showed that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. The mice were susceptible to bacterial infection through oral delivery but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal antimicrobial peptides known as cryptdins. {22:Kobayashi et al. (2005)} concluded that the NOD2 protein is a critical mediator of bacterial immunity within the intestine, providing a possible mechanism for NOD2 mutations in Crohn disease. {48:Watanabe et al. (2004)} studied Nod2 -/- mice and determined that intact Nod2 signaling inhibits Tlr2 ({603028})-driven activation of Nfkb (see {164011}), particularly its Rel subunit ({164910}). Nod2 deficiency or the presence of a Crohn disease-like Nod2 mutation increased Tlr2-mediated activation of Nfkb-Rel in association with enhanced Th1 responses. {48:Watanabe et al. (2004)} concluded that NOD2 signaling normally inhibits TLR2-driven Th1 responses by regulating NFKB signaling. {27:Maeda et al. (2005)} generated mice whose Nod2 locus harbors the homolog of the most common Crohn disease susceptibility allele, 3020insC ({605956.0001}), which encodes a truncated protein lacking the last 33 amino acids. Homozygous Nod2 mutant mice were obtained at the expected mendelian ratio, were healthy, and showed no abnormalities of the gastrointestinal tract or other organs. The mutation had no effect on Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant mice exhibited elevated NFKB activation in response to bacteria-derived muramyl dipeptide and more efficient processing and secretion of the cytokine interleukin-1-beta (IL1B; {147720}). These effects were linked to increased susceptibility to bacteria-induced intestinal inflammation and identified NOD2 as a positive regulator of NFKB activation and IL1B secretion. By histopathologic analysis, {7:Divangahi et al. (2008)} showed that Nod2-deficient mice had reduced inflammatory responses but similar bacterial counts compared with wildtype mice in the first 2 months after infection with Mycobacterium tuberculosis. Nod2-deficient mice infected with the M. bovis BCG vaccine had decreased production of Tnf, Ifng, and Il12p40 (IL12B; {161561}) and reduced recruitment of Cd4 ({186940})-positive and Cd8 (see {186910})-positive T cells. After 6 months, the bacterial burden was increased in the Nod2-deficient mice and their survival was significantly reduced. {7:Divangahi et al. (2008)} concluded that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity. {15:Hruz et al. (2009)} found that Nod2-deficient mice exhibited a delayed but ultimately exacerbated response to subcutaneous Staphylococcus aureus infection. Nod2 action was dependent on Il1b-amplified production of Il6 ({147620}), which promoted rapid bacterial killing by neutrophils. {15:Hruz et al. (2009)} concluded that NOD2 is not only involved in recognition of organisms in cytoplasm, but that it also contributes to recognition of pathogenic bacteria in the extracellular compartment that elaborate pore-forming toxins. T helper-17 (Th17) cells are a subset of CD4-positive helper T cells characterized by secretion of IL17 ({603149}) and IL22 ({605330}). {9:Geddes et al. (2011)} infected mice with Citrobacter rodentium or Salmonella typhimurium species and observed triggering of early Il17 production that was crucial for host defense mediated by Cd4-positive helper T cells. Th17 responses occurred principally in the cecum and were mediated by innate Th17 cells that were regulated by Nod1 and Nod2. Mice lacking both Nod1 and Nod2 were unable to induce early Th17 responses due to insufficient Il6 production. {9:Geddes et al. (2011)} concluded that the NOD-innate Th17 axis, which is dependent on IL6 expression and requires intestinal microbiota for induction, is a key element of mucosal immunity against bacterial pathogens. textSectionName animalModel geneMapExists true editHistory mgross : 09/30/2014 mcolton : 9/22/2014 alopez : 6/2/2014 alopez : 3/14/2013 alopez : 7/24/2012 terry : 7/23/2012 terry : 6/8/2012 terry : 6/8/2012 alopez : 5/1/2012 alopez : 2/28/2012 terry : 2/27/2012 mgross : 8/9/2011 terry : 8/5/2011 mgross : 9/30/2010 mgross : 9/30/2010 terry : 9/28/2010 mgross : 2/15/2010 mgross : 2/15/2010 terry : 2/4/2010 mgross : 1/8/2010 mgross : 1/8/2010 terry : 1/7/2010 wwang : 6/22/2009 ckniffin : 6/2/2009 alopez : 10/31/2008 carol : 8/28/2008 carol : 8/14/2008 wwang : 12/7/2007 ckniffin : 11/30/2007 ckniffin : 11/29/2007 mgross : 11/1/2007 terry : 10/31/2007 alopez : 7/24/2007 alopez : 6/4/2007 terry : 5/31/2007 alopez : 5/16/2007 wwang : 1/26/2007 wwang : 1/23/2007 terry : 1/16/2007 wwang : 6/1/2006 terry : 5/24/2006 alopez : 2/15/2006 terry : 1/20/2006 mgross : 11/7/2005 terry : 10/27/2005 wwang : 9/1/2005 wwang : 7/26/2005 ckniffin : 7/11/2005 carol : 7/5/2005 wwang : 3/23/2005 terry : 3/21/2005 terry : 3/15/2005 wwang : 3/3/2005 terry : 2/25/2005 terry : 6/28/2004 alopez : 5/28/2004 carol : 5/5/2004 terry : 5/3/2004 alopez : 4/28/2004 alopez : 4/27/2004 tkritzer : 4/22/2004 terry : 4/21/2004 terry : 4/9/2004 tkritzer : 4/7/2004 tkritzer : 4/7/2004 tkritzer : 4/5/2004 terry : 4/2/2004 alopez : 10/8/2003 alopez : 9/8/2003 terry : 9/5/2003 tkritzer : 5/9/2003 tkritzer : 5/7/2003 terry : 5/2/2003 terry : 4/25/2003 carol : 3/10/2003 tkritzer : 3/6/2003 terry : 3/3/2003 alopez : 2/26/2003 terry : 2/26/2003 carol : 10/2/2002 tkritzer : 10/1/2002 tkritzer : 10/1/2002 tkritzer : 9/24/2002 tkritzer : 9/12/2002 tkritzer : 9/12/2002 tkritzer : 7/30/2002 tkritzer : 7/29/2002 tkritzer : 7/26/2002 terry : 7/17/2002 cwells : 7/9/2002 terry : 6/26/2002 carol : 5/8/2002 alopez : 4/25/2002 cwells : 4/17/2002 terry : 4/12/2002 carol : 3/1/2002 terry : 3/1/2002 alopez : 11/5/2001 alopez : 8/27/2001 alopez : 8/27/2001 terry : 8/23/2001 joanna : 7/3/2001 joanna : 7/2/2001 mgross : 5/30/2001 mgross : 5/30/2001 mgross : 5/22/2001 mgross : 5/22/2001 dateCreated Tue, 22 May 2001 03:00:00 EDT creationDate Paul J. Converse : 5/22/2001 epochUpdated 1412060400 dateUpdated Tue, 30 Sep 2014 03:00:00 EDT referenceList reference articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1074-7613(13)00387-7 publisherName Elsevier Science title The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. mimNumber 605956 referenceNumber 1 publisherAbbreviation ES pubmedID 24054330 source Immunity 39: 521-536, 2013. authors Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=16000642 publisherName HighWire Press title Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? mimNumber 605956 referenceNumber 2 publisherAbbreviation HighWire pubmedID 16000642 source Gut 55: 342-347, 2006. authors Buhner, S., Buning, C., Genschel, J., Kling, K., Herrmann, D., Dignass, A., Kuechler, I., Krueger, S., Schmidt, H. H.-J., Lochs, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12626759 publisherName HighWire Press title Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. mimNumber 605956 referenceNumber 3 publisherAbbreviation HighWire pubmedID 12626759 source Proc. Nat. Acad. Sci. 100: 3455-3460, 2003. authors Chamaillard, M., Philpott, D., Girardin, S. E., Zouali, H., Lesage, S., Chareyre, F., Bui, T. H., Giovannini, M., Zaehringer, U., Penard-Lacronique, V., Sansonetti, P. J., Hugot, J.-P., Thomas, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nm.2069 publisherName Nature Publishing Group title NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. mimNumber 605956 referenceNumber 4 publisherAbbreviation NPG pubmedID 19966812 source Nature Med. 16: 90-97, 2010. authors Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., Campbell, B. J., Jewell, D., Simmons, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200897 publisherName Nature Publishing Group title Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. mimNumber 605956 referenceNumber 5 publisherAbbreviation NPG pubmedID 12529700 source Europ. J. Hum. Genet. 11: 6-16, 2003. authors Croucher, P. J. P., Mascheretti, S., Hampe, J., Huse, K., Frenzel, H., Stoll, M., Lu, T., Nikolaus, S., Yang, S.-K., Krawczak, M., Kim, W. H., Schreiber, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.john-libbey-eurotext.fr/medline.md?issn=1167-1122&vol=18&iss=6&page=635 publisherName John Libbey Eurotext title Leg ulcers: a new symptom of Blau syndrome? mimNumber 605956 referenceNumber 6 publisherAbbreviation JLE pubmedID 18955195 source Europ. J. Derm. 18: 635-637, 2008. authors Dhondt, V., Hofman, S., Dahan, K., Beele, H. pubmedImages false articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=18981137 publisherName HighWire Press title NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. mimNumber 605956 referenceNumber 7 publisherAbbreviation HighWire pubmedID 18981137 source J. Immun. 181: 7157-7165, 2008. authors Divangahi, M., Mostowy, S., Coulombe, F., Kozak, R., Guillot, L., Veyrier, F., Kobayashi, K. S., Flavell, R. A., Gros, P., Behr, M. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.20209 publisherName John Wiley & Sons, Inc. title Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients. mimNumber 605956 referenceNumber 8 publisherAbbreviation Wiley pubmedID 12923865 source Am. J. Med. Genet. 121A: 240-244, 2003. authors Fidder, H. H., Olschwang, S., Avidan, B., Zouali, H., Lang, A., Bardan, E., Picard, O., Bar-Meir, S., Colombel, J. F., Chowers, Y. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/nm.2391 publisherName Nature Publishing Group title Identification of an innate T helper type 17 response to intestinal bacterial pathogens. mimNumber 605956 referenceNumber 9 publisherAbbreviation NPG pubmedID 21666695 source Nature Med. 17: 837-844, 2011. authors Geddes, K., Rubino, S. J., Magalhaes, J. G., Streutker, C., Le Bourhis, L., Cho, J. H., Robertson, S. J., Kim, C. J., Kaul, R., Philpott, D. J., Girardin, S. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201130 publisherName Nature Publishing Group title Analysis of the CARD15 variants R702W, G908R and L1007fs in Italian IBD patients. mimNumber 605956 referenceNumber 10 publisherAbbreviation NPG pubmedID 14747834 source Europ. J. Hum. Genet. 12: 206-212, 2004. authors Giachino, D., van Duist, M. M., Regazzoni, S., Gregori, D., Bardessono, M., Salacone, P., Scaglione, N., Sostegni, R., Sapone, N., Bresso, F., Sambataro, A., Gaia, E., Pera, A., Astegiano, M., De Marchi, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-8711&volume=14&issue=4&spage=361 publisherName Lippincott Williams & Wilkins title Current concepts in psoriatic arthritis. mimNumber 605956 referenceNumber 11 publisherAbbreviation LWW pubmedID 12118168 source Curr. Opin. Rheum. 14: 361-366, 2002. authors Gladman, D. D. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=17698784 publisherName HighWire Press title Rasmussen syndrome and CNS granulomatous disease with NOD2/CARD15 mutations. mimNumber 605956 referenceNumber 12 publisherAbbreviation HighWire pubmedID 17698784 source Neurology 69: 640-643, 2007. authors Goyal, M., Cohen, M. L., Bangert, B. A., Robinson, S., Singer, N. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(00)05063-7 publisherName Elsevier Science title Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. mimNumber 605956 referenceNumber 13 publisherAbbreviation ES pubmedID 11425413 source Lancet 357: 1925-1928, 2001. Note: Erratum: Lancet 360: 806 only, 2002. authors Hampe, J., Cuthbert, A., Croucher, P. J. P., Mirza, M. M., Mascheretti, S., Fisher, S., Frenzel, H., King, K., Hasselmeyer, A., MacPherson, A. J. S., Bridger, S., van Deventer, S., Forbes, A., Nikolaus, S., Lennard-Jones, J. E., Foelsch, U. R., Krawczak, M., Lewis, C., Schreiber, S., Mathew, C. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(02)08590-2 publisherName Elsevier Science title Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study. mimNumber 605956 referenceNumber 14 publisherAbbreviation ES pubmedID 12020527 source Lancet 359: 1661-1665, 2002. authors Hampe, J., Grebe, J., Nikolaus, S., Solberg, C., Croucher, P. J. P., Mascheretti, S., Jahnsen, J., Moum, B., Klump, B., Krawczak, M., Mirza, M. M., Foelsch, U. R., Vatn, M., Schreiber, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=19541630 publisherName HighWire Press title NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation. mimNumber 605956 referenceNumber 15 publisherAbbreviation HighWire pubmedID 19541630 source Proc. Nat. Acad. Sci. 106: 12873-12878, 2009. authors Hruz, P., Zinkernagel, A. S., Jenikova, G., Botwin, G. J., Hugot, J.-P., Karin, M., Nizet, V., Eckmann, L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/35079107 publisherName Nature Publishing Group title Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. mimNumber 605956 referenceNumber 16 publisherAbbreviation NPG pubmedID 11385576 source Nature 411: 599-603, 2001. authors Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., {and 8 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1111/j.0022-202X.2004.22341.x publisherName Nature Publishing Group title Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation. mimNumber 605956 referenceNumber 17 publisherAbbreviation NPG pubmedID 15086578 source J. Invest. Derm. 122: 851-852, 2004. authors Kanazawa, N., Matsushima, S., Kambe, N., Tachibana, T., Nagai, S., Miyachi, Y. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=15459013 publisherName HighWire Press title Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa-B activation: common genetic etiology with Blau syndrome. mimNumber 605956 referenceNumber 18 publisherAbbreviation HighWire pubmedID 15459013 source Blood 105: 1195-1197, 2005. authors Kanazawa, N., Okafuji, I., Kambe, N., Nishikomori, R., Nakata-Hizume, M., Nagai, S., Fuji, A., Yuasa, T., Manki, A., Sakurai, Y., Nakajima, M., Kobayashi, H., Fujiwara, I., Tsutsumi, H., Utani, A., Nishigori, C., Heike, T., Nakahata, T., Miyachi, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60510-2 publisherName Elsevier Science title A susceptibility gene for psoriatic arthritis maps to chromosome 16p: evidence for imprinting. mimNumber 605956 referenceNumber 19 publisherAbbreviation ES pubmedID 12474146 source Am. J. Hum. Genet. 72: 125-131, 2003. authors Karason, A., Gudjonsson, J. E., Upmanyu, R., Antonsdottir, A. A., Hauksson, V. B., Runasdottir, E. H., Jonsson, H. H., Gudbjartsson, D. F., Frigge, M. L., Kong, A., Stefansson, K., Valdimarsson, H., Gulcher, J. R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(07)00178-4 publisherName Elsevier Science title Identification, evolution, and association study of a novel promoter and first exon of the human NOD2 (CARD15) gene. mimNumber 605956 referenceNumber 20 publisherAbbreviation ES pubmedID 17719742 source Genomics 90: 493-501, 2007. authors King, K., Bagnall, R., Fisher, S. A., Sheikh, F., Cuthbert, A., Tan, S., Mundy, N. I., Rosenstiel, P., Schreiber, S., Mathew, C. G., Roberts, R. G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/humu.20264 publisherName John Wiley & Sons, Inc. title Mutation, selection, and evolution of the Crohn disease susceptibility gene CARD15. mimNumber 605956 referenceNumber 21 publisherAbbreviation Wiley pubmedID 16278823 source Hum. Mutat. 27: 44-54, 2006. authors King, K., Sheikh, M. F., Cuthbert, A. P., Fisher, S. A., Onnie, C. M., Mirza, M. M., Pattni, R. C., Sanderson, J., Forbes, A., Mansfield, J., Lewis, C. M., Roberts, R. G., Mathew, C. G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=15692051 publisherName HighWire Press title Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. mimNumber 605956 referenceNumber 22 publisherAbbreviation HighWire pubmedID 15692051 source Science 307: 731-734, 2005. authors Kobayashi, K. S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., Flavell, R. A. pubmedImages false publisherUrl http://highwire.stanford.edu title Increased occurrence of psoriasis in patients with Crohn's disease and their relatives. mimNumber 605956 referenceNumber 23 pubmedID 2375323 source Am. J. Gastroent. 85: 962-963, 1990. authors Lee, F. I., Bellary, S. V., Francis, C. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60292-4 publisherName Elsevier Science title CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. mimNumber 605956 referenceNumber 24 publisherAbbreviation ES pubmedID 11875755 source Am. J. Hum. Genet. 70: 845-857, 2002. authors Lesage, S., Zouali, H., Cezard, J.-P., {EPWG-IBD Group}, Colombel, J.-F., {EPIMAD Group}, Belaiche, J., {GETAID Group}, Almer, S., Tysk, C., O'Morain, C., Gassull, M., Binder, V., Finkel, Y., Modigliani, R., Gower-Rousseau, C., Macry, J., Merlin, F., Chamaillard, M., Jannot, A.-S., Thomas, G., Hugot, J.-P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15198989 publisherName HighWire Press title Regulation of IL-8 and IL-1-beta expression in Crohn's disease associated NOD2/CARD15 mutations. mimNumber 605956 referenceNumber 25 publisherAbbreviation HighWire pubmedID 15198989 source Hum. Molec. Genet. 13: 1715-1725, 2004. authors Li, J., Moran, T., Swanson, E., Julian, C., Harris, J., Bonen, D. K., Hedl, M., Nicolae, D. L., Abraham, C., Cho, J. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=22344438 publisherName HighWire Press title A systematic survey of loss-of-function variants in human protein-coding genes. mimNumber 605956 referenceNumber 26 publisherAbbreviation HighWire pubmedID 22344438 source Science 335: 823-828, 2012. Note: Erratum: Science 336: 296 only, 2012. authors MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J. K., Montgomery, S. B., Albers, C. A., Zhang, Z. D., {and 40 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=15692052 publisherName HighWire Press title Nod2 mutation in Crohn's disease potentiates NF-kappa-B activity and IL-1-beta processing. mimNumber 605956 referenceNumber 27 publisherAbbreviation HighWire pubmedID 15692052 source Science 307: 734-738, 2005. Note: Erratum: Science 308: 633 only, 2005. Note: Erratum: Science 333: 288 only, 2011. authors Maeda, S., Hsu, L.-C., Liu, H., Bankston, L. A., Iimura, M., Kagnoff, M. F., Eckmann, L., Karin, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201576 publisherName Nature Publishing Group title Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations. mimNumber 605956 referenceNumber 28 publisherAbbreviation NPG pubmedID 16493449 source Europ. J. Hum. Genet. 14: 459-468, 2006. authors Medici, V., Mascheretti, S., Croucher, P. J. P., Stoll, M., Hampe, J., Grebe, J., Sturniolo, G. C., Solberg, C., Jahnsen, J., Moum, B., Schreiber, S., Vatn, M. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng720 publisherName Nature Publishing Group title CARD15 mutations in Blau syndrome. mimNumber 605956 referenceNumber 29 publisherAbbreviation NPG pubmedID 11528384 source Nature Genet. 29: 19-20, 2001. authors Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.-M., Manouvrier-Hanu, S., Hafner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.-P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1007/s00251-002-0440-1 publisherName Springer title CARD15 gene and the classification of Crohn's disease. mimNumber 605956 referenceNumber 30 publisherAbbreviation Springer pubmedID 11976792 source Immunogenetics 54: 59-61, 2002. authors Murillo, L., Crusius, J. B. A., van Bodegraven, A. A., Alizadeh, B. Z., Pena, A. S. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9259283 publisherName HighWire Press title Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. mimNumber 605956 referenceNumber 31 publisherAbbreviation HighWire pubmedID 9259283 source Hum. Molec. Genet. 6: 1349-1356, 1997. authors Nair, R. P., Henseler, T., Jenisch, S., Stuart, P., Bichakjian, C. K., Lenk, W., Westphal, E., Guo, S.-W., Christophers, E., Voorhees, J. J., Elder, J. T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nature13133 publisherName Nature Publishing Group title Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. mimNumber 605956 referenceNumber 32 publisherAbbreviation NPG pubmedID 24695226 source Nature 509: 240-244, 2014. authors Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Maziere, A., Klumperman, J., Schlatter, M., Delamarre, L., Mellman, I. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16115863 publisherName HighWire Press title The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also to Nod1-activating peptidoglycan agonists. mimNumber 605956 referenceNumber 33 publisherAbbreviation HighWire pubmedID 16115863 source J. Biol. Chem. 280: 35859-35867, 2005. authors Netea, M. G., Ferwerda, G., de Jong, D. J., Werts, C., Boneca, I. G., Jehanno, M., Van Der Meer, J. W. M., Mengin-Lecreulx, D., Sansonetti, P. J., Philpott, D. J., Dharancy, S., Girardin, S. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/35079114 publisherName Nature Publishing Group title A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease. mimNumber 605956 referenceNumber 34 publisherAbbreviation NPG pubmedID 11385577 source Nature 411: 603-606, 2001. authors Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nunez, G., Cho, J. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11087742 publisherName HighWire Press title Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappa-B. mimNumber 605956 referenceNumber 35 publisherAbbreviation HighWire pubmedID 11087742 source J. Biol. Chem. 276: 4812-4818, 2001. authors Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., Nunez, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888754303000272 publisherName Elsevier Science title Genetic variation and activity of mouse Nod2, a susceptibility gene for Crohn's disease. mimNumber 605956 referenceNumber 36 publisherAbbreviation ES pubmedID 12676561 source Genomics 81: 369-377, 2003. authors Ogura, Y., Saab, L., Chen, F. F., Benito, A., Inohara, N., Nunez, G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=14560001 publisherName HighWire Press title Role of Nod2 in the response of macrophages to Toll-like receptor agonists. mimNumber 605956 referenceNumber 37 publisherAbbreviation HighWire pubmedID 14560001 source Molec. Cell. Biol. 23: 7531-7539, 2003. authors Pauleau, A.-L., Murray, P. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62032-1 publisherName Elsevier Science title CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. mimNumber 605956 referenceNumber 38 publisherAbbreviation ES pubmedID 12879366 source Am. J. Hum. Genet. 73: 677-681, 2003. authors Rahman, P., Bartlett, S., Siannis, F., Pellett, F. J., Farewell, V. T., Peddle, L., Schentag, C. T., Alderdice, C. A., Hamilton, S., Khraishi, M., Tobin, Y., Hefferton, D., Gladman, D. D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng.952 publisherName Nature Publishing Group title Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. mimNumber 605956 referenceNumber 39 publisherAbbreviation NPG pubmedID 21983784 source Nature Genet. 43: 1066-1073, 2011. authors Rivas, M. A., Beaudoin, M., Gardet, A., Stevens, C., Sharma, Y., Zhang, C. K., Boucher, G., Ripke, S., Ellinghaus, D., Burtt, N., Fennell, T., Kirby, A., {and 29 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1345 publisherName Nature Publishing Group title Genetic variation in DLG5 is associated with inflammatory bowel disease. mimNumber 605956 referenceNumber 40 publisherAbbreviation NPG pubmedID 15107852 source Nature Genet. 36: 476-480, 2004. authors Stoll, M., Corneliussen, B., Costello, C. M., Waetzig, G. H., Mellgard, B., Koch, W. A., Rosenstiel, P., Albrecht, M., Croucher, P. J. P., Seegert, D., Nikolaus, S., Hampe, J., Lengauer, T., Pierrou, S., Foelsch, U. R., Mathew, C. G., Lagerstrom-Fermer, M., Schreiber, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60567-9 publisherName Elsevier Science title A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. mimNumber 605956 referenceNumber 41 publisherAbbreviation ES pubmedID 12577202 source Am. J. Hum. Genet. 72: 509-518, 2003. authors Sugimura, K., Taylor, K. D., Lin, Y., Hang, T., Wang, D., Tang, Y.-M., Fischel-Ghodsian, N., Targan, S. R., Rotter, J. I., Yang, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61889-8 publisherName Elsevier Science title Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families. mimNumber 605956 referenceNumber 42 publisherAbbreviation ES pubmedID 15024686 source Am. J. Hum. Genet. 74: 623-636, 2004. authors Tukel, T., Shalata, A., Present, D., Rachmilewitz, D., Mayer, L., Grant, D., Risch, N., Desnick, R. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201404 publisherName Nature Publishing Group title A new CARD15 mutation in Blau syndrome. mimNumber 605956 referenceNumber 43 publisherAbbreviation NPG pubmedID 15812565 source Europ. J. Hum. Genet. 13: 742-747, 2005. authors van Duist, M. M., Albrecht, M., Podswiadek, M., Giachino, D., Lengauer, T., Punzi, L., De Marchi, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12928481 publisherName HighWire Press title The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants. mimNumber 605956 referenceNumber 44 publisherAbbreviation HighWire pubmedID 12928481 source Hum. Molec. Genet. 12: 2569-2575, 2003. authors van Heel, D. A., Dechairo, B. M., Dawson, G., McGovern, D. P. B., Negoro, K., Carey, A. H., Cardon, L. R., Mackay, I., Jewell, D. P., Lench, N. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(05)66582-8 publisherName Elsevier Science title Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. (Letter) mimNumber 605956 referenceNumber 45 publisherAbbreviation ES pubmedID 15910952 source Lancet 365: 1794-1796, 2005. authors van Heel, D. A., Ghosh, S., Butler, M., Hunt, K. A., Lundberg, A. M. C., Ahmad, T., McGovern, D. P. B., Onnie, C., Negoro, K., Goldthorpe, S., Foxwell, B. M. J., Mathew, C. G., Forbes, A., Jewell, D. P., Playford, R. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.10588 publisherName John Wiley & Sons, Inc. title Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. mimNumber 605956 referenceNumber 46 publisherAbbreviation Wiley pubmedID 12210321 source Am. J. Med. Genet. 111: 253-259, 2002. authors van Heel, D. A., McGovern, D. P. B., Cardon, L. R., Dechairo, B. M., Lench, N. J., Carey, A. H., Jewell, D. P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60036-6 publisherName Elsevier Science title CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. mimNumber 605956 referenceNumber 47 publisherAbbreviation ES pubmedID 12019468 source Am. J. Hum. Genet. 71: 74-83, 2002. authors Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M. J., Rioux, J. D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ni1092 publisherName Nature Publishing Group title NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. mimNumber 605956 referenceNumber 48 publisherAbbreviation NPG pubmedID 15220916 source Nature Immun. 5: 800-808, 2004. authors Watanabe, T., Kitani, A., Murray, P. J., Strober, W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature05911 publisherName Nature Publishing Group title Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. mimNumber 605956 referenceNumber 49 publisherAbbreviation NPG pubmedID 17554300 source Nature 447: 661-678, 2007. authors {Wellcome Trust Case Control Consortium} pubmedImages false publisherUrl http://www.nature.com title Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. mimNumber 605956 referenceNumber 50 pubmedID 12202985 source J. Hum. Genet. 47: 469-472, 2002. Note: Erratum: J. Hum. Genet. 48: 397 only, 2003. authors Yamazaki, K., Takazoe, M., Tanaka, T., Ichimori, T., Nakamura, Y. pubmedImages false externalLinks mgiIDs MGI:2429397 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 11545911,530424183 refSeqAccessionIDs NG_007508.1 dermAtlas false hprdIDs 05810 swissProtIDs Q9HC29 zfinIDs ZDB-GENE-061108-4 uniGenes Hs.592072 gtr true cmgGene false ensemblIDs ENSG00000167207,ENST00000300589 umlsIDs C1826449 genbankNucleotideSequences 37575484,115606181,511793353,14488148,71516170,16508849,37778128,37778129,37778130,307829323,37778131,16508847,37778132,37778133,37778134,37778135,14277249,37778136,389307053,37778139,37778140,37778141,37778142,37778143,162317701,14595637,148191417,14595635,14595633,14595631,11275613,194389735,157170221,14595627,29124038 geneTests true approvedGeneSymbols NOD2 geneIDs 64127 proteinSequences 37575485,115606182,119603173,530424184,20137973,649572336,14595638,14488149,11545912,16508850,14595636,162317702,16508848,14595634,14595632,157170222,14595628,11275614,307829324,578829112,578829116,194389736 geneticsHomeReferenceIDs gene;;NOD2;;NOD2 locusSpecificDBs http://fmf.igh.cnrs.fr/infevers/;;Crohn's Disease & Blau Syndrome; INFEVERS: The repertory of Familial Mediterranean Fever (FMF) and Hereditary Inflammatory Disorders Mutations

entryList

entry status live allelicVariantExists true epochCreated 518079600 geneMap geneSymbols TPI1, TPID sequenceID 8822 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 190450 phenotypeInheritance Autosomal recessive phenotype Hemolytic anemia due to triosephosphate isomerase deficiency phenotypeMimNumber 615512 chromosomeLocationStart 6976287 chromosomeSort 67 chromosomeSymbol 12 mimNumber 190450 geneInheritance None confidence C mappingMethod S, D, R, REa geneName Triosephosphate isomerase-1 mouseMgiID MGI:98797 mouseGeneSymbol Tpi1 computedCytoLocation 12p13.31 cytoLocation 12p13 transcript uc001qrk.4 chromosomeLocationEnd 6980109 chromosome 12 contributors Cassandra L. Kniffin - updated : 6/5/2014 Patricia A. Hartz - updated : 12/1/2006 Victor A. McKusick - updated : 2/26/2002 Victor A. McKusick - updated : 5/13/1999 Victor A. McKusick - updated : 11/30/1998 Victor A. McKusick - updated : 10/14/1997 Alan F. Scott - updated : 11/7/1995 externalLinks cmgGene false mgiHumanDisease true hprdIDs 01833 refSeqAccessionIDs NG_011948.1 uniGenes Hs.524219 approvedGeneSymbols TPI1 nextGxDx false flybaseIDs FBgn0086355 dermAtlas false umlsIDs C1420871 gtr true geneIDs 7167 wormbaseIDs WBGene00160708,WBGene00135457,WBGene00112311,WBGene00054428,WBGene00039902,WBGene00006601 swissProtIDs P60174 zfinIDs ZDB-GENE-020416-4,ZDB-GENE-020416-3 ensemblIDs ENSG00000111669,ENST00000396705 geneTests true diseaseOntologyIDs 0050884 mgiIDs MGI:98797 ncbiReferenceSequences 226529872,384475516,530430081,226529916,530398816 genbankNucleotideSequences 15929331,211948000,339840,300586028,339842,13937949,300567328,1906326,39644503,259701942,39644819,259659112,1633547,47682754,6593459,17403024,123993146,34526034,49456364,194374068,461282,74230026,90914764,40225358,124000136,16877873,148174501,221042393,511799416,300658833,164693677,62896834,259652294,17389814 proteinSequences 211948001,339841,119609127,300586029,14424603,15929332,119609129,119609128,13937950,300567329,259701943,259659113,47682755,384475517,123993147,49456365,194374069,4433249,1200507,189055342,26986678,124000137,16877874,353526311,221042394,300658834,4507645,62896835,226529917,259652295,14043688,17389815,37247,15079577 geneticsHomeReferenceIDs gene;;TPI1;;TPI1 clinicalSynopsisExists false mimNumber 190450 allelicVariantList allelicVariant status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs121964845 text In 2 unrelated patients with TPI deficiency (TPID; {615512}), {10:Daar et al. (1986)} identified a homozygous G-to-C transversion in the TPI1 gene, resulting in a glu104-to-asp (E104D) substitution at a highly conserved residue. The E104D substitution resulted in a thermolabile enzyme. The same homozygous mutation was identified by {9:Chang et al. (1993)} in affected members of 2 Australian families with the disorder. {24:Pekrun et al. (1995)} found a homozygous E104D mutation in a 2-year-old girl, born of consanguineous Turkish parents, with severe TPI deficiency. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced; concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block. {1:Arya et al. (1997)} found that among 7 unrelated northern European kindreds with clinical TPI deficiency, the E104D mutation accounted for 11 (79%) of 14 mutant alleles. In 3 families, molecular analysis revealed compound heterozygosity for E104D novel missense mutations (see {190450.0001} and {190450.0005}). Haplotype analysis indicated a founder effect. {29:Rodriguez-Almazan et al. (2008)} determined that the E104D mutation results in instability of the TPI dimer and causes dissociation of the enzyme into inactive monomers. The substitution does not alter the catalytic residues, but it disrupts a conserved water network that spans the dimer interface and is essential for maintaining TPI dimer stability. mutations TPI1, GLU104ASP number 1 clinvarAccessions RCV000013284;;1 status live name TRIOSEPHOSPHATE ISOMERASE MANCHESTER dbSnps rs121964846 text In a screening of more than 3,400 persons in an Ann Arbor, Michigan, population, {25:Perry and Mohrenweiser (1992)} found only 1 example of a TPI electromorph variant. Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified DNA products and subsequent direct sequencing identified a G-to-A transition causing a gly122-to-arg (G122R) electrophoretic mobility variant of TPI, which was referred to as TPI-Manchester. The substitution was at the amino terminus or solvent interaction end of the fifth beta-sheet of the alpha/beta-barrel structure. TPI-Manchester was found to be thermolabile, but the stability of the variant enzyme was not sensitive to other denaturants. mutations TPI1, GLY122ARG number 2 clinvarAccessions RCV000013285;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs121964847 text In 2 Hungarian brothers with TPID ({615512}), {9:Chang et al. (1993)} identified compound heterozygous mutations in the TPI1 gene: a T-to-C transition, resulting in a phe240-to-leu (F240L) substitution at a highly conserved residue and encoding a thermolabile protein, and an unidentified variant that resulted in reduced TPI mRNA by 10- to 20-fold. This variant has been referred to as TPI-Hungary. The second variant was later identified as E145X ({190450.0006}) ({23:Orosz et al., 2001}). {9:Chang et al. (1993)} determined that the F240L substitution affected enzyme activity by disrupting intersubunit contacts or substrate binding. The family was of clinical interest because the 23-year-old proband had only chronic hemolytic anemia, but no neuromuscular disabilities, whereas his 15-year-old brother had both hemolytic anemia and neuromuscular symptoms. The same family was also reported by {17:Hollan et al. (1993)} who gave clinical details on the 13-year-old boy with congenital hemolytic anemia and hyperkinetic torsion dyskinesia associated with severe TPI deficiency, and on his brother, a 23-year-old amateur wrestler, who also had congenital hemolytic anemia but no neurologic symptoms. ({17:Hollan et al. (1993)} incorrectly referred to the brothers as being double heterozygotes.) Both had less than 10% TPI activity and a greatly increased dihydroxyacetone phosphate (DHAP) level in their red blood cells. Their TPI had a slow electrophoretic mobility and was heat unstable. Both parents and a third brother were healthy heterozygotes. The older brother represented a unique phenotype since all published homozygotes had severe neurologic alterations from infancy or early childhood except 1 infant who died at 11 months, probably too young for neurologic symptoms to be noted. Furthermore, in contrast to the 2 affected Hungarian brothers, all but 1 homozygote had died before the age of 6 years. {23:Orosz et al. (2001)} compared the kinetic, thermodynamic, and associative properties of the recombinant human wildtype and F240L mutant enzymes to those of TPIs in normal and deficient erythrocyte hemolysates. The specific activity of the recombinant mutant enzyme relative to the wildtype was much higher (30%) than expected from the activity (3%) measured in hemolysates. Comparative studies of the hemolysate from a British patient with glu104-to-asp (E104D; {190450.0001}) homozygosity ({4:Ationu et al., 1999}) and the platelet lysates from the Hungarian family suggested that the microcompartmentation of TPI is not unique for the hemolysates from the Hungarian TPI-deficient brothers. mutations TPI1, PHE240LEU number 3 clinvarAccessions RCV000013287;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs121964848 text In 2 families with TPID ({615512}), {1:Arya et al. (1997)} found compound heterozygosity for the common glu104-to-asp mutation (E104D; {190450.0001}) and a previously unknown missense mutation, cys41-to-tyr (C41Y), due to a TGT-to-TAT transition. mutations TPI1, CYS41TYR number 4 clinvarAccessions RCV000013289;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs121964849 text In a family with TPID ({615512}), {1:Arya et al. (1997)} found that affected individuals showed compound heterozygosity for the common glu104-to-asp substitution (E104D; {190450.0001}) and a novel ile170-to-val (I170V) missense mutation. mutations TPI1, ILE170VAL number 5 clinvarAccessions RCV000013290;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs121964850 text See {190450.0003}, {9:Chang et al. (1993)}, and {23:Orosz et al. (2001)}. mutations TPI1, GLU145TER number 6 clinvarAccessions RCV000013291;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs587777440 text In an Italian girl with TPID ({615512}), {13:Fermo et al. (2010)} identified compound heterozygous mutations in the TPI1 gene: a c.722T-C transition, resulting in a phe240-to-ser (F240S) substitution at a highly conserved residue, and the common E104D mutation ({190450.0001}). Each unaffected parent was heterozygous for 1 of the mutations. Patient tissues showed that TPI1 activity was 23% of normal and DHAP levels were 75 times greater than normal. Functional studies of the F240S variant were not performed, but {13:Fermo et al. (2010)} noted that a different mutation at this same codon had been reported (F240L; {190450.0003}). mutations TPI1, PHE240SER number 7 clinvarAccessions RCV000123389;;1 status live name TRIOSEPHOSPHATE ISOMERASE DEFICIENCY dbSnps rs587777441 text In a male infant with TPID ({615512}), {13:Fermo et al. (2010)} identified compound heterozygous mutations in the TPI1 gene: a 1-bp insertion (c.28_29insG), resulting in a frameshift and a premature stop codon at residue 71, and the common E104D mutation ({190450.0001}). The patient had a severe form of the disorder and died at age 10 weeks. TPI activity in the unaffected parents was in the heterozygous range. mutations TPI1, 1-BP INS, 28G number 8 clinvarAccessions RCV000123390;;1 prefix * titles alternativeTitles TPI preferredTitle TRIOSEPHOSPHATE ISOMERASE 1; TPI1 textSectionList textSection textSectionTitle Description textSectionContent The TPI1 gene encodes triosephosphate isomerase (TPI; {EC 5.3.1.1}), a homodimeric enzyme that catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate during glycolysis and gluconeogenesis (summary by {9:Chang et al., 1993}). textSectionName description textSectionTitle Cloning textSectionContent Electrophoretic variants of triosephosphate isomerase were identified by the Galton Laboratory group ({18:Hopkinson and Harris, 1971}). {8:Brown et al. (1985)} isolated the functional gene and 3 intronless pseudogenes for human TPI from a recombinant DNA library. The pseudogenes share a high degree of homology with the functional gene but contain mutations that preclude synthesis of active TPI enzyme. Sequence divergence indicated origin of the pseudogenes about 18 million years ago. {8:Brown et al. (1985)} concluded that the human TPI gene family has only 1 functional gene. {36:Yuan et al. (1979)} concluded on the basis of structural analysis that the TPI-A and TPI-B isozymes are products of distinct structural loci. {11:Decker and Mohrenweiser (1981)} presented evidence that triosephosphate isomerase isozymes are the expression of a single structural locus. (The existence of 2 TPI loci, both probably coded by chromosome 12, had been suggested to explain the observed isozyme patterns.) They identified a rare electrophoretic variant and found that the variant phenotype was expressed in the TPI-B isozyme of both red cells and circulating lymphocytes and was also expressed in the TPI-A isozyme of mitogen-stimulated lymphoblasts. textSectionName cloning textSectionTitle Gene Function textSectionContent TPI is a dimeric enzyme of identical subunits that is characterized by a high constitutive level of activity in all tissues. It is involved in both glycolysis and gluconeogenesis, catalyzing the interconversion of DHAP and glyceraldehyde-3-phosphate. TPI is one of the most efficient enzymes known, enhancing proton transfer by a factor of 10(10), and is the least rate-limiting step in glycolysis (summary by {35:Watanabe et al., 1996}). textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {8:Brown et al. (1985)} found that the functional TPI1 gene spans 3.5 kb and contains 7 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent From study of 3 patients with different deletions of chromosome 12, {27,28:Rethore et al. (1976, 1977)} concluded that the GAPD locus ({138400}) is on the distal part of 12p, between 12p12.2 and 12pter, and that the LDHB locus ({150100}) is on the middle third between 12p12.1 and 12p12.2. The results for TPI were like those for GAPD, suggesting the same distal localization. {20:Law and Kao (1978)} summarized data suggesting the order 12pter--TPI--GAPD--SHMT (SHMT2; {138450}) on chromosome 12. SHMT lies on the proximal part of 12q between the centromere and PEPB ({169900}). {8:Brown et al. (1985)} confirmed that the functional TPI gene is on chromosome 12 whereas the pseudogenes are on other chromosomes. {2:Asakawa and Iida (1985)} also found support for a single TPI locus. GPI ({172400}) and PEPD ({613230}), which are on chromosome 19 in man, are on chromosome 9 of the Chinese hamster, and TPI, which is on chromosome 12 of man, is on Chinese hamster chromosome 8 ({32:Siciliano et al., 1983}). textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {12:Eber et al. (1979)} identified 5 persons heterozygous for a TPI null allele. {22:Maquat et al. (1985)} concluded that the genetic basis of TPI deficiency (TPID; {615512}) is heterogeneous: normal levels of TPI mRNA were found in 1 homozygote and about 40% of normal in another. The rare homozygous deficient persons usually have 3 to 10% of normal enzyme activity. {10:Daar et al. (1986)} and {24:Pekrun et al. (1995)} identified homozygosity for a glu104-to-asp (E104D; {190450.0001}) mutation in the TPI1 gene in patients with triosephosphate isomerase deficiency. {1:Arya et al. (1997)} found that the E104D mutation accounted for 11 (79%) of 14 mutant alleles among 7 unrelated families of northern European origin with TPI deficiency. Haplotype analysis supported a founder effect. Studies by {5:Boyer et al. (1989)} and {6:Boyer and Maquat (1990)} identified several sequences in the 5-prime region that appear to be required for maintenance of normal levels of gene expression. These include a CAP proximal element (CPE) spanning nucleotides -6 and -12. The -5A-G and -8G-A substitutions identified by {35:Watanabe et al. (1996)} are located within the CPE region. The observation that all 7 affected individuals shared the same variant CPE allele, an allele that does not exist at higher frequency in the general African American population, suggested to the authors a common origin for this TPI-deficiency allele; how the allele frequency is maintained at such a high level was unclear. {35:Watanabe et al. (1996)} undertook the molecular characterization of the variant alleles from 7 African American and 3 Caucasian individuals from the unrelated group identified in the frequency studies. In Caucasians they found 3 amino acid substitutions, all in residues that are not directly involved in the enzyme's active site but are highly conserved through evolutionary time, suggesting important roles for these residues in maintenance of subunit structure and conformation. One of the amino acid substitutions, glu104-to-asp ({190450.0001}), had previously been identified in cases of hemolytic anemia due to TPI deficiency. The variant allele in the 7 African American individuals had nucleotide changes at positions -8 and -5 on the 5-prime side of the transcription-initiation site. In a study of 424 African American subjects and 75 white subjects, {31:Schneider et al. (1998)} found that the -5 (592A-G), -8 (382G-A), and -24 (573T-G) variants in the triosephosphate isomerase gene occurred frequently (41%) in the African American subjects but did not occur in whites. These data suggested that this set of polymorphisms may be one of the higher-incidence molecular markers of African lineage. Although the variant substitutions (occurring in 3 haplotypes: -5 alone, -5 -8, and -5 -8 -24) were associated with moderate reduction in enzyme activity, severe deficiency heterozygotes could not be identified with certainty, and none of the haplotypes was restricted to subjects with marked reduction of enzyme activity. Three subjects were homozygous for the -5 -8 haplotype, a finding inconsistent with the putative role of this haplotype as the cause of a null variant incompatible with life in homozygotes, as had been suggested in the past for the rarity of homozygotes with TPI deficiency in African Americans. Despite these findings, {31:Schneider et al. (1998)} admitted the possibility that the -5 -8 or -5 -8 -24 haplotypes may in some instances contribute to compound heterozygosity and clinical TPI deficiency. In 2 unrelated children with TPI deficiency, {13:Fermo et al. (2010)} identified compound heterozygous mutations in the TPI gene. Each patient carried the E104D mutation on 1 allele and a different mutation on the other allele ({190450.0007} and {190450.0008}). textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {14:Gnerer et al. (2006)} identified a recessive hypomorphic mutation in Drosophila, which they called 'wasted away' (wstd), that causes progressive motor impairment, vacuolar neuropathology, and severely reduced life span. They found that wstd was caused by a mutation in the Tpi1 gene. The mutation did not result in a significant deficit in ATP, and the authors suggested that the lack of TPI1 activity may cause the accumulation of toxic metabolites upstream of the enzymatic block. textSectionName animalModel textSectionTitle History textSectionContent TPI was 1 of 4 representative 'ancient' proteins used by {34:Stoltzfus et al. (1994)} to test the exon theory of genes. Spliceosomal introns are present in the nuclear protein-coding genes of most eukaryotic organisms, but they have not been detected in several eukaryotic protist phyla or in eubacteria, archaebacteria, and organelles. Two major theories had emerged in the continuing debate on the origin of these introns. The exon theory of genes (sometimes called the introns-early view) proposed that exons are the descendants of ancient mini-genes and introns are the descendants of the spaces between them; genes large enough to encode contemporary proteins were first assembled from sets of exons; the machinery of splicing originated in an ancient RNA world; and introns were lost completely from both kingdoms of bacteria as well as several protist groups. In contrast, the insertional theory of intron origin (also known as the introns-late view) holds that split genes arise from uninterrupted genes by insertion of introns; genes large enough to encode contemporary proteins first arose (presumably from smaller genes) without the participation of introns; the machinery of spliceosomal splicing arose from fragmented self-splicing introns; and spliceosomal introns were never present in the ancestors of those organisms that now lack them. The analysis performed by {34:Stoltzfus et al. (1994)} on TPI, the globins, pyruvate kinase, and alcohol dehydrogenase demonstrated no significant correspondence between exons and units of protein structure, suggesting that the putative correspondence does not exist and that the exon theory of genes is untenable. The chicken-and-egg question of which came first--exons or introns--was studied, using TPI as a model, also by {19:Kwiatowski et al. (1995)} and {21:Logsdon et al. (1995)}. Each group looked at the positions of introns in homologous TPI genes from a number of phylogenetically diverse species. Both groups concluded that introns were gained comparatively recently in eukaryotic evolution by insertion into preexisting genes. From studies in the cri-du-chat syndrome ({123450}), {33:Sparkes et al. (1969)} suggested that the TPI locus is on the short arm of chromosome 5. Others failed to confirm this ({7:Brock and Singer, 1970}), and the locus was later confirmed to be on chromosome 12 ({8:Brown et al., 1985}). textSectionName history geneMapExists true editHistory carol : 06/13/2014 mcolton : 6/6/2014 ckniffin : 6/5/2014 alopez : 11/7/2013 alopez : 11/7/2013 terry : 2/9/2009 terry : 2/9/2009 wwang : 6/6/2007 wwang : 12/1/2006 wwang : 9/7/2006 mgross : 3/17/2004 mgross : 3/6/2002 terry : 2/26/2002 mgross : 5/19/1999 mgross : 5/17/1999 terry : 5/13/1999 carol : 12/2/1998 terry : 11/30/1998 dkim : 9/11/1998 jenny : 10/24/1997 jenny : 10/21/1997 terry : 10/14/1997 terry : 7/8/1997 jenny : 6/5/1997 mark : 2/23/1996 terry : 2/19/1996 mark : 11/7/1995 mark : 6/27/1995 mimadm : 6/7/1995 terry : 10/27/1994 carol : 4/14/1994 carol : 7/13/1993 dateCreated Mon, 02 Jun 1986 03:00:00 EDT creationDate Victor A. McKusick : 6/2/1986 epochUpdated 1402642800 dateUpdated Fri, 13 Jun 2014 03:00:00 EDT referenceList reference articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)10:4<290::AID-HUMU4>3.0.CO;2-L publisherName John Wiley & Sons, Inc. title Evidence for founder effect of the glu104-to-asp substitution and identification of new mutations in triosephosphate isomerase deficiency. mimNumber 190450 referenceNumber 1 publisherAbbreviation Wiley pubmedID 9338582 source Hum. Mutat. 10: 290-294, 1997. authors Arya, R., Lalloz, M. R. A., Bellingham, A. J., Layton, D. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Origin of human triosephosphate isomerase isozymes: further evidence for the single structural locus hypothesis with Japanese variants. mimNumber 190450 referenceNumber 2 pubmedID 3861565 source Hum. Genet. 71: 22-26, 1985. authors Asakawa, J., Iida, S. pubmedImages false title Electrophoretic variants of blood proteins in Japanese: III. Triosephosphate isomerase. mimNumber 190450 referenceNumber 3 pubmedID 6500570 source Hum. Genet. 68: 185-188, 1984. authors Asakawa, J., Satoh, C., Takahashi, N., Fujita, M., Kaneko, J., Goriki, K., Hazama, R., Kageoka, T. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(99)00474-2 publisherName Elsevier Science title Towards enzyme-replacement treatment in triosephosphate isomerase deficiency. mimNumber 190450 referenceNumber 4 publisherAbbreviation ES pubmedID 10209987 source Lancet 353: 1155-1156, 1999. authors Ationu, A., Humphries, A., Wild, B., Carr, T., Will, A., Arya, R., Layton, D. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2925688 publisherName HighWire Press title Transcriptional regulatory sequences of the housekeeping gene for human triosephosphate isomerase. mimNumber 190450 referenceNumber 5 publisherAbbreviation HighWire pubmedID 2925688 source J. Biol. Chem. 264: 5177-5187, 1989. authors Boyer, T. G., Krug, J. R., Maquat, L. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2243103 publisherName HighWire Press title Minimal sequence and factor requirements for the initiation of transcription from an atypical, TATATAA box-containing housekeeping promoter. mimNumber 190450 referenceNumber 6 publisherAbbreviation HighWire pubmedID 2243103 source J. Biol. Chem. 265: 20524-20532, 1990. authors Boyer, T. G., Maquat, L. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Red cell triosephosphate isomerase gene. (Letter) mimNumber 190450 referenceNumber 7 pubmedID 4097939 source Lancet 296: 1136 only, 1970. Note: Originally Volume II. authors Brock, D. J. H., Singer, J. D. pubmedImages false articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=4022011 publisherName HighWire Press title Characterization of the functional gene and several processed pseudogenes in the human triosephosphate isomerase gene family. mimNumber 190450 referenceNumber 8 publisherAbbreviation HighWire pubmedID 4022011 source Molec. Cell. Biol. 5: 1694-1706, 1985. authors Brown, J. R., Daar, I. O., Krug, J. R., Maquat, L. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Human triosephosphate isomerase deficiency resulting from mutation of phe-240. mimNumber 190450 referenceNumber 9 pubmedID 8503454 source Am. J. Hum. Genet. 52: 1260-1269, 1993. authors Chang, M.-L., Artymiuk, P. J., Wu, X., Hollan, S., Lammi, A., Maquat, L. E. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2876430 publisherName HighWire Press title Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. mimNumber 190450 referenceNumber 10 publisherAbbreviation HighWire pubmedID 2876430 source Proc. Nat. Acad. Sci. 83: 7903-7907, 1986. authors Daar, I. O., Artymiuk, P. J., Phillips, D. C., Maquat, L. E. pubmedImages false publisherUrl http://highwire.stanford.edu source Hum. Genet. 33: 683-691, 1981. mimNumber 190450 authors Decker, R. S., Mohrenweiser, H. W. title Origin of the triosephosphate isomerase isozymes in humans: genetic evidence for the expression of a single structural locus. referenceNumber 11 title Hereditary deficiency of triosephosphate isomerase in four unrelated families. mimNumber 190450 referenceNumber 12 pubmedID 113220 source Europ. J. Clin. Invest. 9: 195-202, 1979. authors Eber, S. W., Dunnwald, M., Belohradsky, B. H., Bidlingmaier, F., Schievelbein, H., Weinmann, H. M., Krietsch, W. K. G. pubmedImages false articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0902-4441&date=2010&volume=85&issue=2&spage=170 publisherName Blackwell Publishing title Triose phosphate isomerase deficiency associated with two novel mutations in TPI gene. mimNumber 190450 referenceNumber 13 publisherAbbreviation Blackwell pubmedID 20374271 source Europ. J. Haemat. 85: 170-173, 2010. authors Fermo, E., Bianchi, P., Vercellati, C., Rees, D. C., Marcello, A. P., Barcellini, W., Zanella, A. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17008404 publisherName HighWire Press title wasted away, a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death. mimNumber 190450 referenceNumber 14 publisherAbbreviation HighWire pubmedID 17008404 source Proc. Nat. Acad. Sci. 103: 14987-14993, 2006. authors Gnerer, J. P., Kreber, R. A., Ganetzky, B. pubmedImages false publisherUrl http://highwire.stanford.edu title Studies on human triosephosphate isomerase. II. Characterization of the enzyme from patients with the cri du chat syndrome. mimNumber 190450 referenceNumber 15 pubmedID 4716662 source Am. J. Hum. Genet. 25: 433-438, 1973. authors Hendrickson, R. J., Snapka, R. M., Sawyer, T. H., Gracy, R. W. pubmedImages false title Chromosomal assignment and regional localization of CS, ENO-2, GAPDH, LDH-B, PEPB, and TPI in man-rodent cell hybrids. mimNumber 190450 referenceNumber 16 pubmedID 318158 source Cytogenet. Cell Genet. 22: 482-486, 1978. authors Herbschleb-Voogt, E., Monteba-van Heuvel, M., Wijnen, L. M. M., Westerveld, A., Pearson, P. L., Meera Khan, P. pubmedImages false title Hereditary triosephosphate isomerase (TPI) deficiency: two severely affected brothers one with and one without neurological symptoms. mimNumber 190450 referenceNumber 17 pubmedID 8244340 source Hum. Genet. 92: 486-490, 1993. authors Hollan, S., Fujii, H., Hirono, A., Hirono, K., Karro, H., Miwa, S., Harsanyi, V., Gyodi, E., Inselt-Kovacs, M. pubmedImages false articleUrl http://arjournals.annualreviews.org/doi/full/10.1146/annurev.ge.05.120171.000253?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Recent work on isozymes in man. mimNumber 190450 referenceNumber 18 publisherAbbreviation ATYPON pubmedID 16097649 source Ann. Rev. Genet. 5: 5-32, 1971. authors Hopkinson, D. A., Harris, H. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7667319 publisherName HighWire Press title Evidence against the exon theory of genes derived from the triose-phosphate isomerase gene. mimNumber 190450 referenceNumber 19 publisherAbbreviation HighWire pubmedID 7667319 source Proc. Nat. Acad. Sci. 92: 8503-8506, 1995. authors Kwiatowski, J., Krawczyk, M., Kornacki, M., Bailey, K., Ayala, F. J. pubmedImages false publisherUrl http://highwire.stanford.edu title Induced segregation of human syntenic genes by 5-bromodeoxyuridine plus near-visible light. mimNumber 190450 referenceNumber 20 pubmedID 684558 source Somat. Cell Genet. 4: 465-476, 1978. authors Law, M. L., Kao, F.-T. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7667320 publisherName HighWire Press title Seven newly discovered intron positions in the triose-phosphate isomerase gene: evidence for the introns-late theory. mimNumber 190450 referenceNumber 21 publisherAbbreviation HighWire pubmedID 7667320 source Proc. Nat. Acad. Sci. 92: 8507-8511, 1995. authors Logsdon, J. M., Jr., Tyshenko, M. G., Dixon, C., D.-Jafari, J., Walker, V. K., Palmer, J. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2579079 publisherName HighWire Press title Human triosephosphate isomerase cDNA and protein structure: studies of triosephosphate isomerase deficiency in man. mimNumber 190450 referenceNumber 22 publisherAbbreviation HighWire pubmedID 2579079 source J. Biol. Chem. 260: 3748-3753, 1985. authors Maquat, L. E., Chilcote, R., Ryan, P. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11698297 publisherName HighWire Press title Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency. mimNumber 190450 referenceNumber 23 publisherAbbreviation HighWire pubmedID 11698297 source Blood 98: 3106-3112, 2001. authors Orosz, F., Olah, J., Alvarez, M., Keseru, G. M., Szabo, B., Wagner, G., Kovari, Z., Horanyi, M., Baroti, K., Martial, J. A., Hollan, S., Ovadi, J. pubmedImages false publisherUrl http://highwire.stanford.edu title Triosephosphate isomerase deficiency: biochemical and molecular genetic analysis for prenatal diagnosis. mimNumber 190450 referenceNumber 24 pubmedID 7628118 source Clin. Genet. 47: 175-179, 1995. authors Pekrun, A., Neubauer, B. A., Eber, S. W., Lakomek, M., Seidel, H., Schroter, W. pubmedImages false title Human triosephosphate isomerase: substitution of arg for gly at position 122 in a thermolabile electromorph variant, TPI-Manchester. mimNumber 190450 referenceNumber 25 pubmedID 1339398 source Hum. Genet. 88: 634-638, 1992. authors Perry, B. A., Mohrenweiser, H. W. pubmedImages false title Genetic and non-genetic variations of triose phosphate isomerase isozymes in human tissues. mimNumber 190450 referenceNumber 26 pubmedID 4714420 source Ann. Hum. Genet. 36: 297-312, 1973. authors Peters, J., Hopkinson, D. A., Harris, H. pubmedImages false title Localisation du gene de la glyceraldehyde 3-phosphate deshydrogenase (G3PD) sur le segment distal du bras court du chromosome 12. mimNumber 190450 referenceNumber 27 pubmedID 1085604 source Ann. Genet. 19: 140-142, 1976. authors Rethore, M.-O., Junien, C., Malpuech, G., Baccichetti, C., Tenconi, R., Kaplan, J.-C., de Romeuf, J., Lejeune, J. pubmedImages false title 12pter-12p12.2: Possible assignment of human triosephosphate isomerase. mimNumber 190450 referenceNumber 28 pubmedID 858628 source Hum. Genet. 36: 235-237, 1977. authors Rethore, M.-O., Kaplan, J.-C., Junien, C., Lejeune, J. pubmedImages false articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18562316 publisherName HighWire Press title Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface. mimNumber 190450 referenceNumber 29 publisherAbbreviation HighWire pubmedID 18562316 source J. Biol. Chem. 283: 23254-23263, 2008. authors Rodriguez-Almazan, C., Arreola, R., Rodriguez-Larrea, D., Aguirre-Lopez, B., de Gomez-Puyou, M. T., Perez-Montfort, R., Costas, M., Gomez-Puyou, A., Torres-Larios, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Triosephosphate isomerase gene not localized on the short arm of chromosome 5 in man. (Letter) mimNumber 190450 referenceNumber 30 pubmedID 5488105 source Nature 228: 1320-1321, 1970. authors Rudiger, H. W., Passarge, E., Hirth, L., Goedde, H. W., Blume, K. G., Lohr, G. W., Benohr, H. C., Waller, H. D. pubmedImages false articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=9763583 publisherName HighWire Press title The relationship of the -5, -8, and -24 variant alleles in African Americans to triosephosphate isomerase (TPI) enzyme activity and to TPI deficiency. mimNumber 190450 referenceNumber 31 publisherAbbreviation HighWire pubmedID 9763583 source Blood 92: 2959-2962, 1998. authors Schneider, A., Forman, L., Westwood, B., Yim, C., Lin, J., Singh, S., Beutler, E. pubmedImages false publisherUrl http://highwire.stanford.edu title Provisional assignment of TPI, GPI, and PEPD to Chinese hamster autosomes 8 and 9: a cytogenetic basis for functional haploidy of an autosomal linkage group in CHO cells. mimNumber 190450 referenceNumber 32 pubmedID 6825466 source Cytogenet. Cell Genet. 35: 15-20, 1983. authors Siciliano, M. J., Stallings, R. L., Adair, G. M., Humphrey, R. M., Siciliano, J. pubmedImages false title Probable localization of a triosephosphate isomerase gene to the short arm of number 5 human chromosome. mimNumber 190450 referenceNumber 33 pubmedID 5343881 source Nature 224: 367-398, 1969. authors Sparkes, R. S., Carrel, R. E., Paglia, D. E. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8023140 publisherName HighWire Press title Testing the exon theory of genes: the evidence from protein structure. mimNumber 190450 referenceNumber 34 publisherAbbreviation HighWire pubmedID 8023140 source Science 265: 202-207, 1994. authors Stoltzfus, A., Spencer, D. F., Zuker, M., Logsdon, J. M., Jr., Doolittle, W. F. pubmedImages false publisherUrl http://highwire.stanford.edu title Molecular analysis of a series of alleles in humans with reduced activity at the triosephosphate isomerase locus. mimNumber 190450 referenceNumber 35 pubmedID 8571957 source Am. J. Hum. Genet. 58: 308-316, 1996. authors Watanabe, M., Zingg, B. C., Mohrenweiser, H. W. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0003-9861(79)90393-X publisherName Elsevier Science title Isolation and characterization of triosephosphate isomerase isozymes from human placenta. mimNumber 190450 referenceNumber 36 publisherAbbreviation ES pubmedID 507849 source Arch. Biochem. Biophys. 198: 42-52, 1979. authors Yuan, P. M., Dewan, R. N., Zaun, M., Thompson, R. E., Gracy, R. W. pubmedImages false publisherUrl http://www.elsevier.com/ seeAlso Asakawa et al. (1984); Hendrickson et al. (1973); Herbschleb-Voogt et al. (1978); Peters et al. (1973); Rudiger et al. (1970)

entryList

entry status live allelicVariantExists true epochCreated 1081148400 geneMap geneSymbols SH2D1A, LYP, IMD5, XLP, XLPD1 sequenceID 14934 phenotypeMapList phenotypeMap phenotypeMimNumber 308240 mimNumber 300490 phenotypeInheritance X-linked recessive phenotypicSeriesMimNumber 308240 phenotypeMappingKey 3 phenotype Lymphoproliferative syndrome, X-linked, 1 chromosomeLocationStart 123480131 chromosomeSort 588 chromosomeSymbol X mimNumber 300490 geneInheritance None confidence C mappingMethod Fd, D geneName SH2 domain protein 1A comments 1cM from DXS42; no recombination with DXS37 mouseMgiID MGI:1328352 mouseGeneSymbol Sh2d1a computedCytoLocation Xq25 cytoLocation Xq25 transcript uc004euf.4 chromosomeLocationEnd 123507009 chromosome 23 contributors Paul J. Converse - updated : 9/16/2013 Patricia A. Hartz - updated : 1/21/2011 Paul J. Converse - updated : 8/30/2010 Paul J. Converse - updated : 11/19/2008 Paul J. Converse - updated : 3/12/2008 Paul J. Converse - updated : 8/31/2007 Paul J. Converse - updated : 10/20/2006 Paul J. Converse - updated : 10/17/2006 Paul J. Converse - updated : 9/19/2006 Marla J. F. O'Neill - updated : 3/29/2005 Victor A. McKusick - updated : 3/21/2005 Paul J. Converse - updated : 6/18/2004 externalLinks cmgGene false mgiHumanDisease false hprdIDs 02390 nbkIDs NBK1406;;Lymphoproliferative Disease, X-Linked refSeqAccessionIDs NG_007464.1,NG_033796.2 uniGenes Hs.349094 approvedGeneSymbols SH2D1A nextGxDx true locusSpecificDBs http://www.LOVD.nl/SH2D1A;;CCHMC - Human Genetics Mutation Database;;;http://structure.bmc.lu.se/idbase/SH2D1Abase/;;SH2D1Abase: Mutation registry for X-linked lymphoproliferative syndrome (XLP) dermAtlas false umlsIDs C1420017 gtr true geneIDs 4068 swissProtIDs O60880 zfinIDs ZDB-GENE-060526-212,ZDB-GENE-091204-326 ensemblIDs ENSG00000183918,ENST00000371139 geneTests true mgiIDs MGI:1328352 ncbiReferenceSequences 295054104,295054105 genbankNucleotideSequences 511784705,511784706,3928895,164696981,49457014,3928893,78290814,123996976,307133521,3153107,3695068,18088433,3695070,157928975,148155708,1777266,164698042,148155704,148155705,148155706,148155707,34555385,3763969,3928899,218630130,253776410,3928897,423091980,49457038,74230033,3928901 proteinSequences 3928894,49457015,123996977,169234945,6094278,119632253,307133522,119632252,119632255,119632254,119632256,3153108,3695069,18088434,3695071,189053230,4506923,3928898,157928976,423091981,218630131,253776411,3928896,3928902,49457039,3928900 geneticsHomeReferenceIDs gene;;SH2D1A;;SH2D1A clinicalSynopsisExists false mimNumber 300490 allelicVariantList allelicVariant status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033623 text In a patient with X-linked lymphoproliferative disease ({308240}), {6:Coffey et al. (1998)} identified a 462C-T transition in the SH2D1A gene, resulting in an arg55-to-ter (R55X) substitution in the middle of the SH2 domain. In 2 of 4 patients with XLP, {11:Lappalainen et al. (2000)} identified the R55X mutation. They noted that the mutation involves a CpG dinucleotide and suggested that nucleotide 462 is a mutation hotspot in the SH2D1A gene. mutations SH2D1A, ARG55TER number 1 clinvarAccessions RCV000011645;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033628 text In a patient with XLP ({308240}), {6:Coffey et al. (1998)} identified a 471C-T transition in the SH2D1A cDNA, resulting in a gln58-to-ter (Q58X) substitution. mutations SH2D1A, GLN58TER number 2 clinvarAccessions RCV000011646;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 text In 2 brothers with XLP ({308240}), {6:Coffey et al. (1998)} identified a 159-bp deletion following nucleotide 448 of the SH2D1A gene, which removed a 3-prime 53 bp of exon 2 and the 5-prime 106 bp of intronic sequence. This deletion removed 18 amino acids from the center of the SH2 domain, as well as the donor splice site at the end of the exon. mutations SH2D1A, 159-BP DEL number 3 clinvarAccessions RCV000011647;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033624 text In a male with XLP ({308240}), {6:Coffey et al. (1998)} identified a 394G-C transversion in the SH2D1A gene, resulting in an arg32-to-thr (R32T) substitution. The presence of an arginine at position 32 in the SH2 domain is critical for phosphotyrosine binding. mutations SH2D1A, ARG32THR number 4 clinvarAccessions RCV000011648;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 text In 2 affected brothers with XLP ({308240}), {6:Coffey et al. (1998)} identified a 500G-T transversion in the SH2D1A gene. The change was in the last nucleotide of the exon, changing the splice site from AGgt to ATgt. RNA was not available; however, it was predicted that the mutation would inhibit correct splicing, as the mutation resulted in a reduction in the splice site score ({28:Shapiro and Senapathy, 1987}) from 81.8 (normal) to 69.0. mutations SH2D1A, IVS2AS, G-T, -1 number 5 clinvarAccessions RCV000011649;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033625 text In a patient with XLP ({308240}), {6:Coffey et al. (1998)} identified a 684T-A transversion in the SH2D1A gene, changing the normal termination codon to an arginine (X129R), resulting in an addition of 12 amino acids to the C terminus of the protein. The authors suggested that the C-terminal extension disrupts the folding of the SH2 domain or interferes with the interaction between the SH2 domain and its phosphotyrosine target. Alternatively, this mutation may disrupt an as yet unknown function of the normal C-terminal tail of the protein. mutations SH2D1A, TER129ARG number 6 clinvarAccessions RCV000011650;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033626 text In a patient with XLP ({308240}), {6:Coffey et al. (1998)} identified a 601C-T transition in the SH2D1A gene, resulting in a pro101-to-leu (P101L) amino acid substitution. The mutation was also demonstrated in 2 obligate carriers in the kindred. mutations SH2D1A, PRO101LEU number 7 clinvarAccessions RCV000011651;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033627 text In a patient with XLP ({308240}), {6:Coffey et al. (1998)} identified a 502C-T transition in the SH2D1A gene, resulting in a thr68-to-ile (T68I) amino acid substitution. mutations SH2D1A, THR68ILE number 8 clinvarAccessions RCV000011652;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 text In a patient with XLP ({308240}), {6:Coffey et al. (1998)} identified a C-to-T transition of position -10 in the promoter region of the SH2D1A gene, changing a potential CCAAT box to CTAAT. mutations SH2D1A, -10C-T number 9 clinvarAccessions RCV000011653;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 text In 2 brothers with XLP ({308240}) who presented with B-cell non-Hodgkin lymphoma without evidence of Epstein-Barr virus infection, {4:Brandau et al. (1999)} and {30:Strahm et al. (2000)} identified a deletion in the first exon of the SH2D1A gene. The brothers presented at ages 4 and 2 years, respectively. mutations SH2D1A, EX1DEL number 10 clinvarAccessions RCV000011654;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033629 text In a family with multiple XLP ({308240}) deaths from fulminant hepatitis or leukemia after EBV infection, {19:Parolini et al. (2000)} identified a G-to-T transversion at nucleotide 3 in the translation initiation codon of the SH2D1A gene, resulting in a met1-to-ile substitution. The mutation was demonstrated in a healthy 3-year-old and in obligate carriers in the kindred. mutations SH2D1A, MET1ILE number 11 clinvarAccessions RCV000011655;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 text In a patient with XLP ({308240}) and in his 2 asymptomatic nephews, {19:Parolini et al. (2000)} identified a 163C-to-T transition in the SH2D1A gene, leading to a premature termination at codon 55. mutations SH2D1A, 163C-T number 12 clinvarAccessions RCV000011656;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs111033630 text {3:Benoit et al. (2000)} identified an arg55-to-leu mutation in the second exon of the SH2D1A gene in autopsy specimens from 2 maternally related cousins diagnosed with XLP ({308240}). They also identified the mutation in 2 healthy, EBV-seronegative males in the extended family. Based on the molecular structure of the SH2D1A-SLAM ({603492}) interaction, this mutation was predicted to disrupt binding between the SH2 domain of SH2D1A and the cytoplasmic domain of SLAM. The mutation was also predicted to interfere with SH2D1A-2B4 ({605554}) binding because of the strong amino acid homology shared by SLAM and 2B4. mutations SH2D1A, ARG55LEU number 13 clinvarAccessions RCV000011657;;1 status live name LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1 dbSnps rs587777612 text {23:Recher et al. (2013)} reported a 2-year-old Caucasian boy of nonconsanguineous parents who developed recurrent suppurative otitis media at 8 months of age followed by other bacterial and viral, but not EBV, infections. At 13 months of age, no serum IgG, IgA, or IgM was detectable, and B-cell levels were below normal. At 17 and 24 months of age, IgA and IgM remained undetectable, but B-cell numbers were within normal range. NKT cells were undetectable. At 3 years of age, EBV viremia was found as part of a pre-bone marrow transplant evaluation, but it remained clinically silent and resolved after B-cell depleting therapy. Sequencing of the SH2D1A gene revealed a G-C transversion at position +5 in intron 1. Patient SH2D1A mRNA was of normal length and sequence, but its expression was reduced 10-fold compared with a healthy control. Western blot analysis showed reduced expression of a normal-sized SH2D1A protein. Flow cytometric analysis demonstrated virtual abrogation of SH2D1A expression. Sequence analysis of the parental SH2D1A genes revealed the mother to be the carrier of the mutation, with wildtype sequence in the father. mutations SH2D1A, IVS1DS, G-C, +5 number 14 clinvarAccessions RCV000133459;;1 prefix * titles alternativeTitles SIGNALING LYMPHOCYTE ACTIVATION MOLECULE-ASSOCIATED PROTEIN;; SLAM-ASSOCIATED PROTEIN; SAP preferredTitle SH2 DOMAIN PROTEIN 1A; SH2D1A textSectionList textSection textSectionTitle Cloning textSectionContent By positional cloning, {6:Coffey et al. (1998)} identified the gene mutated in X-linked lymphoproliferative disease (XLP; {308240}). The SH2 domain protein-1A (SH2D1A) gene encodes a deduced 128-amino acid protein consisting of a 5-amino acid N-terminal sequence, an SH2 domain, and a 25-amino acid C-terminal tail. The absence of a hydrophobic signal sequence suggests that SH2D1A is localized in the cytoplasm. Northern blot analysis detected a 2.5-kb SH2D1A mRNA expressed at high levels in thymus and lung, with a lower level of expression in spleen and liver. SH2D1A expression was also detected by RT-PCR in all lymphocyte populations assayed, but was not detected in a range of EBV-transformed lymphoblastoid cell lines. To determine the signaling mechanism of SLAM (signaling lymphocyte activation molecule; {603492}), a glycosylated transmembrane protein also known as CDw150 or CD150, {26:Sayos et al. (1998)} identified the SH2D1A gene, which they referred to as SAP for 'SLAM-associated protein.' The predicted 128-amino acid human SAP protein is 96% homologous to the murine protein in both the SH2 and tail domains. In both humans and in mice, SAP is expressed in all major subsets of T cells, including CD4+, CD45RO+, CD45RA+, and CD8+, but not in B cells. textSectionName cloning textSectionTitle Gene Structure textSectionContent {6:Coffey et al. (1998)} determined that the SH2D1A gene contains 4 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent By positional cloning, {6:Coffey et al. (1998)} identified the SH2D1A gene within the X-linked lymphoproliferative disease critical region on Xq25. Using a clone that contained all 4 exons of mouse Sap, {26:Sayos et al. (1998)} localized the gene to the part of the mouse X chromosome corresponding to human Xq25. textSectionName mapping textSectionTitle Biochemical Features textSectionContent {11:Lappalainen et al. (2000)} developed a 3-dimensional model of the SH2 domain of the SH2D1A protein. textSectionName biochemicalFeatures textSectionTitle Gene Function textSectionContent SLAM is a protein that is centrally involved in the bidirectional stimulation of T and B cells. When activated, it mediates expansion of activated T cells during immune responses, induces production of interferon-gamma, and changes the functional profile of subsets of T cells. Signaling through SLAM-SLAM binding during mutual interaction between B cells, and between B cells and T cells, increases the expansion and differentiation of activated B cells. {26:Sayos et al. (1998)} found that SAP binding blocks the recruitment of the tyrosine phosphatase SHP2 ({176876}) to the phosphorylated cytoplasmic domain of SLAM, suggesting that SAP is a natural inhibitor of SLAM. Upon T-cell activation, SLAM may switch from a signaling cascade that is dependent on SAP, and probably on FYN ({137025}), a member of the src tyrosine kinase family, to one that depends on SHP2. {26:Sayos et al. (1998)} proposed that SAP controls the signal-transduction pathways initiated by interactions between SLAM molecules at the interface between T and B cells. {26:Sayos et al. (1998)} showed that SAP cDNAs isolated from the blood cells of patients with X-linked lymphoproliferative syndrome did not bind SLAM. {21:Poy et al. (1999)} described 3-dimensional protein structures showing that SH2D1A binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine- or phosphotyrosine-281 residue inserted into the phosphotyrosine-binding pocket. Specific interactions with residues N-terminal to this tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. SH2D1A interacts via its SH2 domain with the protein sequence motif TIpYXX(V/I). A phosphopeptide library screen and analysis of mutations identified in XLP patients confirmed that these extended interactions are required for SH2D1A function. Using binding analysis, {35:Tangye et al. (1999)} found that phosphorylated 2B4 ({605554}), a protein with significant homology to SLAM, recruits either SHP2 or SAP. {34:Sylla et al. (2000)} reported that SH2D1A associates with DOK1 ({602919}), a protein that interacts with RAS-GAP, cytoplasmic tyrosine kinase (CSK; {124095}), and NCK (see NCK1; {600508}). They found that an SH2D1A SH domain mutant found in XLP does not associate with Dok1, suggesting this interaction is linked to XLP. Other evidence indicated that SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus (EBV) infection. {15:Morra et al. (2001)} stated that SH2D1A interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150 (SLAM), CD84 ({604513}), CD229 (LY9; {600684}), and CD244 (2B4). {15:Morra et al. (2001)} analyzed the effect of SH2D1A protein missense mutations identified in 10 XLP families and found that the mutant proteins clustered into 2 major groups: mutants with a markedly decreased half-life, and mutants with structural changes that variably affect their interaction with the 4 receptors. Because there was no correlation between the type of mutation and clinical presentation, {15:Morra et al. (2001)} concluded that unidentified genetic or environmental factors must play a strong role in XLP disease manifestations. {10:Hwang et al. (2002)} screened a repertoire of synthetic peptides and stated that the consensus motif for binding is T/SXXXXV/I. This motif is unusual in that it contains neither a tyrosine nor a phosphotyrosine residue, hallmarks of conventional SH2 domain-ligand interactions. The NMR-determined structures of the protein in complex with 2 distinct peptides provided direct evidence in support of a '3-pronged,' more versatile, binding mechanism for the SH2D1A SH2 domain, in contrast to the '2-pronged' binding for conventional SH2 domains. {10:Hwang et al. (2002)} noted that all of the mutants examined in their study showed markedly reduced affinities for the nonphosphorylated SLAM peptide, suggesting that phosphorylation-independent interactions mediated by SH2D1A likely play an important role in the pathogenesis of XLP. Using an array of peptides derived from the SLAM family of receptors, {13:Li et al. (2003)} demonstrated that SH2D1A binds with comparable affinities to the same sites in those receptors as do the SH2 domains of SHP2 and SH2-containing inositol phosphatase (SHIP; {601582}), suggesting that the 3 proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicated that SH2D1A is capable of binding directly to the T cell-specific tyrosine kinase FYN ({137025}), an interaction mediated by the FYN SH3 domain. In cells, FYN was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was dramatically enhanced by SH2D1A. Because SH2D1A also blocked the recruitment of SHP2 to SLAM, {13:Li et al. (2003)} proposed a dual functional role for SH2D1A in SLAM signaling, acting as both an adaptor for FYN and an inhibitor to SHP2 binding. They concluded that this dual role is likely to be physiologically relevant, since disease-causing SH2D1A mutants exhibited significantly reduced affinities to both FYN and SLAM. The cytoplasmic protein encoded by the SH2D1A gene plays an essential role in controlling EBV infection. It is expressed in T and NK cells, but not in B cells or in granulocytes. {18:Parolini et al. (2003)} tested the hypothesis that DNA methylation contributes to tissue-specific SH2D1A gene expression and analyzed the methylation status of 2,300 bp upstream of the ATG starting codon, the coding region, and part of intron 1. By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, they showed that a differential methylation pattern of CpG-rich regions in the 5-prime region and the adjacent exon 1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription. By studying NK-cell function in patients with XLP and a defect in the SAP gene, {19:Parolini et al. (2000)} found that a number of triggering receptors displayed normal function. However, upon 2B4 interaction with CD48 ({109530}), NK-cell function against EBV-infected cells, which is primarily mediated via NKp46 (LY94; {604530}), was inhibited. Disruption of 2B4-CD48 and/or NK receptor-HLA interaction restored NK cytolytic activity. RT-PCR analysis detected the full-length 2B4 cDNA as well as a 2B4 molecule lacking the Ig C2 domain in both patients and normal individuals. Molecular analysis failed to reveal any differences between normal and patient 2B4 sequences. Immunoblot analysis showed that treatment of normal but not XLP NK cells with pervanadate led to the association of 2B4 with SAP. {19:Parolini et al. (2000)} suggested that anti-2B4 treatment might be of use in XLPD patients awaiting bone marrow transplantation. {36:Tangye et al. (2000)} found that although XLP patient NK cells can be active, the absence of SAP selectively cripples the 2B4-mediated activation pathway. XLPD patient NK cells were unable to lyse CD48-expressing target cells. The authors pointed out that CD48 was originally identified as an antigen whose expression is at least 10-fold greater on EBV-transformed cells than on EBV-negative cells ({37:Thorley-Lawson et al., 1982}). {1:Aoukaty and Tan (2005)} found that NK cells from individuals with XLP due to SAP mutations failed to phosphorylate GSK3A ({606784}) and GSK3B ({605004}) after stimulation of 2B4. Lack of GSK3 phosphorylation inactivated GSK3 and prevented accumulation of the transcriptional coactivator beta-catenin (CTNNB1; {116806}) in the cytoplasm and its subsequent translocation to the nucleus. {1:Aoukaty and Tan (2005)} identified VAV1 ({164875}), RAC1 ({602048}), RAF1 ({164760}), MEK2 (MAP2K2; {601263}), ERK1 (MAPK3; {601795}), and ERK3 (MAPK6; {602904}) as proteins potentially involved in mediating the signaling pathway between 2B4 and GSK3/CTNNB and found that some of these elements were aberrant in XLP NK cells. {1:Aoukaty and Tan (2005)} concluded that GSK3 and beta-catenin mediate signaling of 2B4 in NK cells and that dysfunction of some of the elements in the transduction pathway between 2B4 and GSK3/beta-catenin may result in diminished IFNG ({147570}) secretion and cytotoxic function of NK cells in XLP patients. {12:Latour et al. (2001)} reported that antibody-mediated ligation of SLAM on thymocytes triggered a protein tyrosine phosphorylation signal in T cells in a SAP-dependent manner. This signal also involved SHIP; the adaptor molecules DOK2 ({604997}), DOK1, and SHC ({600560}); and RASGAP (see {139150}). SAP was crucial for this pathway because it selectively recruited and activated the T-cell isoform of FYN. {25:Sanzone et al. (2003)} showed that T cells from patients with XLP were deficient in expression of the activation marker CD25 (IL2RA; {147730}) and in IL2 ({147680}) production in response to T-cell receptor (TCR) stimulation, but not in response to TCR-independent stimulation by phorbol ester. The activation deficiency was associated with diminished VAV and MAP kinase phosphorylation, and it could be reversed by retroviral-mediated SAP gene transfer. Using yeast 2-hybrid, immunoblot, and structural analyses, {5:Chan et al. (2003)} showed that the SH2 domain of SAP bound to the SH3 domain of FYN in a noncanonical manner and directly coupled FYN to SLAM. {17:Nichols et al. (2005)} observed that Sh2d1a -/- mice lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell-autonomous and could be rescued by reconstitution of Sh2d1a expression within Sh2d1a -/- bone marrow cells. {17:Nichols et al. (2005)} also studied 17 individuals with XLP and differing SH2D1A genotypes. All 17 lacked NKT cells, and a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. {17:Nichols et al. (2005)} concluded that SH2D1A is a crucial regulator of NKT cell ontogeny, and that the absence of NKT cells may contribute to the XLP phenotype, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia. Independently, {20:Pasquier et al. (2005)} showed that SAP was required for NKT cell development in mice and humans. They proposed that NKT cells may be important in the immune response to EBV. By studying TCR restimulation of preactivated T cells from EBV-naive XLP patients after prolonged exposure to IL2, {29:Snow et al. (2009)} found that activated T cells from these patients were specifically and substantially less sensitive to restimulation-induced cell death (RICD). Silencing SAP or NTBA (SLAMF6; {606446}) expression recapitulated resistance to RICD in normal T cells, indicating that both molecules are necessary for optimal TCR-induced apoptosis. TCR restimulation triggered increased recruitment of SAP to NTBA, and these proteins functioned to augment TCR-induced signal strength and induction of downstream proapoptotic target genes, including FASL (TNFSF6; {134638}) and BIM (BCL2L11; {603827}). {29:Snow et al. (2009)} proposed that XLP patients are inherently susceptible to antigen-induced lymphoproliferative disease and fulminant infectious mononucleosis due to compromised RICD. {16:Nagy et al. (2009)} found that p53 (TP53; {191170}) was upregulated in activated T cells, and they had previously shown that p53 induces SAP expression in lymphoid cells. Expression of SAP in the Saos-2 human osteosarcoma cell line, which lacks p53, was required to control cell proliferation after irradiation-induced DNA damage. High SAP expression rendered T-ALL tumor cell lines more sensitive to activation-induced cell death, and lymphoblastic cell lines developed from healthy donors, but not those from XLP patients, arrested in G2/M phase of the cell cycle following irradiation. {16:Nagy et al. (2009)} concluded that SAP may be involved in the termination of T-cell responses via activation-induced cell death. They proposed that the absence of functional SAP in XLP patients may allow extended survival of overactivated T cells in infectious mononucleosis, leading to the massive tissue infiltrates and organ failures seen in fatal infectious mononucleosis. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent In 9 unrelated patients with X-linked lymphoproliferative syndrome, {6:Coffey et al. (1998)} identified mutations in the SH2D1A gene ({300490.0001}-{300490.0009}). {32:Sumegi et al. (1999)} reviewed the molecular basis of Duncan disease and tabulated 15 mutations in the SH2D1A gene. In 2 brothers with early-onset non-Hodgkin lymphoma, but no clinical or laboratory evidence of EBV infection, {4:Brandau et al. (1999)} identified a deletion of exon 1 of the SH2D1A gene ({300490.0010}). Other SH2D1A mutations were identified in 2 additional unrelated patients without evidence of EBV infection; 1 had non-Hodgkin lymphoma and 1 had signs of dysgammaglobulinemia. Development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggested that EBV is unrelated to these particular phenotypes, in contrast to fulminant or fatal infectious mononucleosis. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP. By PCR, RT-PCR, and sequence analysis of genetic material from 19 typical and 8 atypical XLP patients, {40:Yin et al. (1999)} identified 13 mutations in the SH2D1A gene. One atypical patient reported by {40:Yin et al. (1999)} had initially been diagnosed as having B-cell leukemia, and the diagnosis of XLP was ascertained only after detection of an SH2D1A mutation in the patient's genomic DNA. {4:Brandau et al. (1999)} had identified mutations in the SH2D1A gene in 2 independent B-cell leukemia patients. However, {40:Yin et al. (1999)} concluded that the experience in their atypical XLP patient and the negative result of mutation screening in 62 Burkitt lymphoma cell lines ({41:Yin et al., 1999}) seemed to exclude SH2D1A mutations as causative in B-cell leukemia. {30:Strahm et al. (2000)} described 2 brothers, previously reported by {4:Brandau et al. (1999)}, suffering from recurrent manifestations of B-cell non-Hodgkin lymphoma and recurrent infections of the lower respiratory tract associated with bronchiectasis. Molecular analysis of the SH2D1A gene led to the identification of a deletion in the first exon ({300490.0010}) in both patients. {30:Strahm et al. (2000)} postulated that the genetic defect identified in the 2 EBV-seronegative brothers with non-Hodgkin lymphoma ({300490.0010}) resulted in a dysregulation of the B-/T-cell interaction, rendering these patients susceptible to the early onset of B-cell non-Hodgkin lymphoma. Using an SSCP assay for mutation analysis, {11:Lappalainen et al. (2000)} identified mutations in the SH2D1A gene in 4 patients with a clinical history of XLP. Noting that a large proportion of SH2D1A mutations lead to truncation of the produced protein, the authors used molecular modeling to show that truncated SH2D1A proteins do not fold and function correctly even if produced. {33:Sumegi et al. (2000)} reported that analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families: 3 large genomic deletions, 10 small intragenic deletions, 3 splice site, 3 nonsense, and 9 missense mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP), or in 9 patients with chronic active EBV syndrome. The authors found that although EBV infection often resulted in fulminant infectious mononucleosis, it was not necessary for the expression of other manifestations of XLP and correlated poorly with outcome. They interpreted the results as suggesting that unidentified factors, either environmental or genetic (e.g., modifier genes), contribute to the pathogenesis of XLP. The phenotype of hemophagocytic lymphohistiocytosis (HPLH; {267700}) bears a strong resemblance to X-linked lymphoproliferative disease. For that reason, {2:Arico et al. (2001)} analyzed 25 patients diagnosed with HPLH for germline mutations in the SH2D1A gene. They identified 4 patients who had XLP and a mutation in the SH2D1A gene. Two had hemizygous deletions encompassing SH2D1A exon 1 ({300490.0010}) and 2 had nonsense mutations. Among these 4 patients, only 2 had family histories consistent with XLP. {31:Sumazaki et al. (2001)} searched for mutations in the SH2D1A gene in 40 males in Japan who presented with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of the patients; 5 of these 10 were sporadic cases. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. In contrast, chronic active EBV infection was not associated with SH2D1A mutations. {24:Ross et al. (2005)} pointed out that discovery of the relationship between X-linked lymphoproliferative disease and the SH2D1A gene is an example of how the identification of genes involved in rare conditions can yield important biologic insights. In this instance, discovery of mutations in the SH2D1A gene led to identification of a new mediator of signal transduction between T and NK cells, and a novel family of proteins involved in the regulation of the immune response. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {39:Wu et al. (2001)} generated Sap-deficient mice, which were fertile and had no defects in lymphocyte surface markers or overall morphology. Sap-deficient mice had increased lymphocytic choriomeningitis virus (LCMV)-specific splenic and hepatic T cells and increased gamma-interferon (IFNG; {147570}) production compared with their wildtype littermates. All Sap-deficient mice died as a result of hepatotropic LCMV infection, while only 30% of wildtype mice died. In contrast to the increased Ifng production, interleukin-4 (IL4; {147780}) production was markedly lower in Sap-deficient mice. Mice with a BALB/c background are normally highly susceptible to infection with the Leishmania major parasite due to poor Ifng production. However, Sap-deficient mice with a BALB/c background produced little Il4 and high levels of Ifng and had lower parasite burdens than wildtype BALB/c mice. This suggested that in the absence of SAP, IL4 gene activation is defective. Lower Il4 expression in Sap-deficient mice correlated with greatly reduced IgE production and reduced basal IgE expression. {39:Wu et al. (2001)} proposed that the Sap-deficient mouse model would be a useful tool for dissecting the complex XLP phenotypes. {8:Czar et al. (2001)} introduced a targeted mutation into the Sh2d1a gene of mice. Mice deficient in SLAM-associated protein had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection with lymphocytic choriomeningitis virus or Toxoplasma gondii was associated with increased T-cell activation and interferon-gamma production, as well as a reduction of immunoglobulin-secreting cells. Anti-CD3-stimulated splenocytes from uninfected mutant mice produced increased IFN-gamma and decreased IL4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggested that cytokine misregulation may contribute to phenotypes associated with mutations of SH2D1A. Using a Sap knockout mouse model, {7:Crotty et al. (2003)} found that Sap-deficient mice generated strong acute IgG antibody responses after lymphocytic choriomeningitis virus infection, but these titers rapidly waned and were accompanied by a paucity of long-lived plasma cells and memory B cells. Virus-specific memory CD4 ({186940})-positive T cells were present in the Sap -/- mice. Histologic analysis demonstrated a severe reduction in the number and size of germinal centers. Using adoptive transfer and cell mixing experiments, {7:Crotty et al. (2003)} showed that the defect resided not in B cells but in the CD4-positive T cells of Sap-deficient mice. They concluded that SAP expression in CD4-positive T cells is essential for generating long-lived plasma cells and memory B cells. {14:Morra et al. (2005)} found that mice lacking Sh2d1a had severely impaired primary and secondary responses of all Ig subclasses to specific antigens, even in the absence of viral infection. Fluorescence microscopy demonstrated that Sh2d1a was present in germinal centers in spleens of wildtype mice, but that germinal centers were absent in Sh2d1a-deficient mice after primary immunization. Adoptive transfer experiments showed that Sh2d1a expression was required in both B and T lymphocytes for responses to soluble T-dependent antigens. {14:Morra et al. (2005)} proposed that, in the absence of SH2D1A, progressive dysgammaglobulinemia can occur in XLP patients without the involvement of EBV. Using 2-photon intravital imaging, {22:Qi et al. (2008)} showed that Sap deficiency in mice selectively impaired the ability of Cd4-positive T cells to interact with B lymphocytes, but not dendritic cells. This selective defect resulted in diminished levels of contact-dependent T-cell help, even though these T cells possessed other characteristics of competent helper T cells. Sap -/- T cells also displayed impaired recruitment to and retention in nascent germinal centers. {22:Qi et al. (2008)} concluded that the germinal center defect arising from Sap deficiency is caused by the inability of T cells to interact and communicate with cognate B cells, while interaction of T cells with dendritic cells remains unaffected. They proposed that SLAM family members may have a role in T- and B-cell interactions, and {9:Deenick and Tangye (2008)}, in a commentary, suggested that the SLAM family member CD84 ({604513}) is a promising candidate. Using a conditional gene targeting approach in mice and intracellular flow cytometric analysis, {38:Veillette et al. (2008)} showed that the defects in antibody production and memory B-cell generation in Sap-deficient mice, and presumably humans with XLP, resulted from lack of Sap expression in T cells, but not in B cells or NK cells. textSectionName animalModel geneMapExists true editHistory alopez : 08/19/2014 mgross : 9/16/2013 mgross : 9/16/2013 mgross : 2/9/2011 terry : 1/21/2011 mgross : 10/4/2010 terry : 8/30/2010 mgross : 11/19/2008 terry : 11/19/2008 mgross : 3/13/2008 terry : 3/12/2008 mgross : 10/29/2007 mgross : 10/29/2007 terry : 8/31/2007 alopez : 1/16/2007 mgross : 10/20/2006 mgross : 10/20/2006 terry : 10/17/2006 mgross : 9/20/2006 terry : 9/19/2006 terry : 8/3/2005 wwang : 3/30/2005 wwang : 3/29/2005 alopez : 3/24/2005 terry : 3/21/2005 carol : 10/1/2004 mgross : 6/18/2004 carol : 5/26/2004 carol : 5/26/2004 carol : 5/26/2004 ckniffin : 4/14/2004 dateCreated Mon, 05 Apr 2004 03:00:00 EDT creationDate Cassandra L. Kniffin : 4/5/2004 epochUpdated 1408431600 dateUpdated Tue, 19 Aug 2014 03:00:00 EDT referenceList reference articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15814676 publisherName HighWire Press title Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease. mimNumber 300490 referenceNumber 1 publisherAbbreviation HighWire pubmedID 15814676 source J. Immun. 174: 4551-4558, 2005. authors Aoukaty, A., Tan, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11159547 publisherName HighWire Press title Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. mimNumber 300490 referenceNumber 2 publisherAbbreviation HighWire pubmedID 11159547 source Blood 97: 1131-1133, 2001. authors Arico, M., Imashuku, S., Clementi, R., Hibi, S., Teramura, T., Danesino, C., Haber, D. A., Nichols, K. 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M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ncb920 publisherName Nature Publishing Group title SAP couples Fyn to SLAM immune receptors. mimNumber 300490 referenceNumber 5 publisherAbbreviation NPG pubmedID 12545174 source Nature Cell Biol. 5: 155-160, 2003. authors Chan, B., Lanyi, A., Song, H. K., Griesbach, J., Simarro-Grande, M., Poy, F., Howie, D., Sumegi, J., Terhorst, C., Eck, M. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/2424 publisherName Nature Publishing Group title Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. mimNumber 300490 referenceNumber 6 publisherAbbreviation NPG pubmedID 9771704 source Nature Genet. 20: 129-135, 1998. authors Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. 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R., Zhang, K., van Hoff, J., Dhar, D., Nichols, K. E., Filipovich, A. H., Su, H. C., Bleesing, J. J., Lenardo, M. J. pubmedImages false publisherUrl http://www.jci.org articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=2000&volume=108&issue=2&spage=377 publisherName Blackwell Publishing title Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection. mimNumber 300490 referenceNumber 30 publisherAbbreviation Blackwell pubmedID 10691868 source Brit. J. Haemat. 108: 377-382, 2000. authors Strahm, B., Rittweiler, K., Duffner, U., Brandau, O., Orlowska-Volk, M., Karajannis, M. A., zur Stadt, U., Tiemann, M., Reiter, A., Brandis, M., Meindl, A., Niemeyer, C. M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11493483 publisherName HighWire Press title SH2D1A mutations in Japanese males with severe Epstein-Barr virus-associated illnesses. mimNumber 300490 referenceNumber 31 publisherAbbreviation HighWire pubmedID 11493483 source Blood 98: 1268-1270, 2001. authors Sumazaki, R., Kanegane, H., Osaki, M., Fukushima, T., Tsuchida, M., Matsukura, H., Shinozaki, K., Kimura, H., Matsui, A., Miyawaki, T. pubmedImages false publisherUrl http://highwire.stanford.edu title The molecular genetics of X-linked lymphoproliferative (Duncan's) disease. mimNumber 300490 referenceNumber 32 pubmedID 10198724 source Cancer J. Sci. Am. 5: 57-62, 1999. authors Sumegi, J., Gross, T. G., Seemayer, T. A. pubmedImages false articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11049992 publisherName HighWire Press title Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. mimNumber 300490 referenceNumber 33 publisherAbbreviation HighWire pubmedID 11049992 source Blood 96: 3118-3125, 2000. authors Sumegi, J., Huang, D., Lanyi, A., Davis, J. D., Seemayer, T. A., Maeda, A., Klein, G., Seri, M., Wakiguchi, H., Purtilo, D. T., Gross, T. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10852966 publisherName HighWire Press title The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62(dok) (Dok1) and activates NF-kappa-beta. mimNumber 300490 referenceNumber 34 publisherAbbreviation HighWire pubmedID 10852966 source Proc. Nat. Acad. Sci. 97: 7470-7475, 2000. authors Sylla, B. S., Murphy, K., Cahir-McFarland, E., Lane, W. S., Mosialos, G., Kieff, E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=10358138 publisherName HighWire Press title Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. mimNumber 300490 referenceNumber 35 publisherAbbreviation HighWire pubmedID 10358138 source J. Immun. 162: 6981-6985, 1999. authors Tangye, S. G., Lazetic, S., Woollatt, E., Sutherland, G. R., Lanier, L. L., Phillips, J. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=10975798 publisherName HighWire Press title Cutting edge: functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. mimNumber 300490 referenceNumber 36 publisherAbbreviation HighWire pubmedID 10975798 source J. Immun. 165: 2932-2936, 2000. authors Tangye, S. G., Phillips, J. H., Lanier, L. L., Nichols, K. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(82)90239-2 publisherName Elsevier Science title Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. mimNumber 300490 referenceNumber 37 publisherAbbreviation ES pubmedID 6291768 source Cell 30: 415-425, 1982. authors Thorley-Lawson, D. A., Schooley, R. T., Bhan, A. K., Nadler, L. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18212118 publisherName HighWire Press title SAP expression in T cells, not in B cells, is required for humoral immunity. mimNumber 300490 referenceNumber 38 publisherAbbreviation HighWire pubmedID 18212118 source Proc. Nat. Acad. Sci. 105: 1273-1278, 2008. authors Veillette, A., Zhang, S., Shi, X., Dong, Z., Davidson, D., Zhong, M.-C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/87713 publisherName Nature Publishing Group title SAP controls T cell responses to virus and terminal differentiation of T(H)2 cells. mimNumber 300490 referenceNumber 39 publisherAbbreviation NPG pubmedID 11323694 source Nature Immun. 2: 410-414, 2001. authors Wu, C., Nguyen, K. B., Pien, G. C., Wang, N., Gullo, C., Duncan, H., Sosa, M. R., Edwards, M. J., Borrow, P., Satoskar, A. R., Sharpe, A. H., Biron, C. A., Terhorst, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://link.springer.de/link/service/journals/00439/bibs/9105005/91050501.htm publisherName Springer title SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. mimNumber 300490 referenceNumber 40 publisherAbbreviation Springer pubmedID 10598819 source Hum. Genet. 105: 501-505, 1999. authors Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G. pubmedImages false publisherUrl http://www.springeronline.com/ source Am. J. Hum. Genet. 65 (suppl. 1868): A331 only, 1999. mimNumber 300490 authors Yin, L., Tocco, T., Pauly, S., Lenoir, G. M., Romeo, G. title Absence of SH2D1A point mutation in 62 Burkitts lymphoma cell lines. referenceNumber 41 seeAlso Scher (1982)

entryList

entry status live allelicVariantExists true epochCreated 890121600 geneMap geneSymbols PON2 sequenceID 5808 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 602447 phenotypeInheritance None phenotype {Coronary artery disease, susceptibility to} chromosomeLocationStart 95034173 chromosomeSort 366 chromosomeSymbol 7 mimNumber 602447 geneInheritance None confidence C mappingMethod REc geneName Paraoxonase-2 mouseMgiID MGI:106687 mouseGeneSymbol Pon2 computedCytoLocation 7q21.3 cytoLocation 7q21.3 transcript uc003unv.3 chromosomeLocationEnd 95064635 chromosome 7 contributors Marla J. F. O'Neill - updated : 2/19/2009 Patricia A. Hartz - updated : 10/29/2008 Victor A. McKusick - updated : 8/26/1998 John A. Phillips, III - updated : 4/22/1998 clinicalSynopsisExists false mimNumber 602447 allelicVariantList allelicVariant status live name PARAOXONASE 2 POLYMORPHISM dbSnps rs7493 text {9:Sanghera et al. (1998)} demonstrated a cys311-to-ser (C311S) polymorphism of the PON2 gene in Asian Indians. The frequency of the PON2*S allele was significantly higher in cases of coronary artery disease than in controls (0.71 vs 0.61). Further stratification of the PON2*S association, on the basis of the presence or absence of the PON1*B allele, showed that the coronary heart disease risk associated with the PON2*S allele was confined to carriers of the PON1*B allele. mutations PON2, CYS311SER number 1 clinvarAccessions RCV000007500;;1 status live name PARAOXONASE 2 POLYMORPHISM dbSnps rs12026 text {2:Hegele et al. (1997)} tested for association between common genomic variation in PON1 ({168820}), PON2, and PDK4 ({602527}), all of which map to chromosome 7q21-q22, and quantitative traits related to NIDDM ({125853}) in a sample of Oji-Cree. They found that a common genomic variation (A to G) in codon 148 (alanine or glycine) of PON2 showed a significant association with variations in fasting plasma glucose. They also found a significant association between a variation in fasting plasma glucose and the interaction term comprised of a PON2 codon 148 variation and the presence of NIDDM. They analyzed subjects according to PON2 genotype and NIDDM status. In subjects with NIDDM, the PON2 codon 148 G/G homozygotes had significantly higher mean fasting plasma glucose than subjects with the other 2 genotypes. There was no association of the PON2 genotype with NIDDM itself, with impaired glucose tolerance, or with other quantitative traits related to NIDDM in this sample. They concluded that the PON2 G148 gene variant worsens glycemia in subjects with NIDDM and that defining the physiologic role of the PON2 gene product would be worthwhile. mutations PON2, ALA148GLY number 2 clinvarAccessions RCV000007501;;1 prefix * titles preferredTitle PARAOXONASE 2; PON2 textSectionList textSection textSectionTitle Description textSectionContent Members of the paraoxonase ({EC 3.1.1.2}) gene family, such as PON2, encode high density lipoprotein (HDL)-related glycoproteins with multienzymatic properties ({4:Lu et al., 2006}). textSectionName description textSectionTitle Cloning textSectionContent {7:Primo-Parmo et al. (1996)} identified 2 human PON1 ({168820})-like genes that they designated PON2 and PON3 ({602720}). In contrast to PON1, which is expressed mainly in the liver, Pon2 was expressed in a variety of mouse tissues, including pancreas. {5:Mochizuki et al. (1998)} found that the PON2 gene was ubiquitously expressed. They identified several mRNA forms produced by alternative splicing or by the use of a second transcription start site. Using SDS-PAGE, {1:Draganov et al. (2005)} found that PON2 had an apparent molecular mass of 39 kD. However, using nondenaturing PAGE, they observed native recombinant PON2 at an apparent molecular mass of 127.5 kD, suggesting that PON2 forms trimers. {4:Lu et al. (2006)} stated that human PON1, PON2, and PON3 have 3 conserved cysteines. Cys41 and cys351 are predicted to form an intramolecular disulfide bond, and cys283 is predicted to be involved in antioxidant activity. textSectionName cloning textSectionTitle Gene Structure textSectionContent {7:Primo-Parmo et al. (1996)} found that the human PON2 gene contains 9 exons spanning 28 kb. textSectionName geneStructure textSectionTitle Mapping textSectionContent All 3 PON genes, including PON2, have been mapped to chromosome 7q21-q22 ({6:Primo-Parmo et al., 1996}, {3:Humbert et al., 1993}). {5:Mochizuki et al. (1998)} showed that PON2 is physically linked to PON1 and PON3 on chromosome 7q21.3. textSectionName mapping textSectionTitle Gene Function textSectionContent {1:Draganov et al. (2005)} found that glycosylation of recombinant PON2 with high-mannose-type sugars did not alter its enzymatic activity, but it may have affected protein stability. They found that PON1, PON2, and PON3, whether expressed in insect or HEK293 cells, metabolized oxidized forms of arachidonic acid and docosahexaenoic acid. Otherwise, the PONs showed distinctive substrate specificities. PON2 showed significantly higher activity against acylhomoserine lactones (AHLs) than the other PONs. While a portion of PON1 and PON3 activity was secreted into the culture medium of transfected HEK293 cells, PON2 lactonase activity remained cell associated. The recombinant PONs did not protect human low density lipoprotein against Cu(2+)-induced oxidation in vitro, and no antioxidant activity copurified with any of the PONs. {1:Draganov et al. (2005)} suggested that, since AHLs are quorum-sensing mediators in bacteria, PON2 may have a role in disrupting quorum sensing by pathogenic bacteria. They noted that upregulation of PON2 expression is associated with oxidative stress accompanying infection and maturation of monocytes to macrophages. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent A common polymorphism at codon 192 in the PON1 gene (Q192R; {168820.0001}) has been shown to be associated with increased risk of coronary heart disease (CHD) in Caucasian populations. However, the failure to find the association consistently in all Caucasian and non-Caucasian populations suggests that it is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. {9:Sanghera et al. (1998)} described a common polymorphism at codon 311 of the PON2 gene: cys311 to ser, which they called PON2*S ({602447.0001}). They found that this polymorphism, alone or in combination with the Q192R polymorphism of the PON1 gene, was associated with CHD in Asian Indians. They presented data indicating that the PON1*B and PON2*S alleles contributed synergistically to the CHD risk in this sample, and that this genetic risk was independent of the conventional plasma lipid profile. In genomewide scanning to identify noninsulin-dependent diabetes mellitus (NIDDM; {125853}) susceptibility genes in Pima Indians, {8:Prochazka et al. (1995)} found linkages of DNA markers at chromosome 7q21.3-q22.1 with both quantitative traits related to glucose uptake and storage and possibly with NIDDM itself. In a sample of Oji-Cree with NIDDM, {2:Hegele et al. (1997)} observed that homozygosity for the PON2 G148 allele (A148G; {602447.0002}) was associated with worsened fasting hyperglycemia. The PON2 variation was not associated with the presence of NIDDM and thus was not interpreted as being causative. {2:Hegele et al. (1997)} suggested that PON2 may be a modifier gene for a complex quantitative phenotype related to NIDDM. {5:Mochizuki et al. (1998)} described 2 polymorphisms in the PON2 coding sequence that predicted an arg147-to-gly substitution and a ser310-to-cys substitution in the protein deduced from the longest open reading frame. For a discussion of an association between diabetic nephropathy and variation in the PON2 gene, see microvascular complications of diabetes-5 ({603933}). textSectionName molecularGenetics geneMapExists true editHistory carol : 02/23/2009 terry : 2/19/2009 mgross : 11/12/2008 mgross : 11/7/2008 mgross : 11/6/2008 mgross : 11/6/2008 terry : 10/29/2008 carol : 8/27/1998 terry : 8/26/1998 alopez : 4/22/1998 alopez : 4/22/1998 alopez : 3/17/1998 psherman : 3/17/1998 dateCreated Tue, 17 Mar 1998 03:00:00 EST creationDate Victor A. McKusick : 3/17/1998 epochUpdated 1235376000 dateUpdated Mon, 23 Feb 2009 03:00:00 EST referenceList reference articleUrl http://www.jlr.org/cgi/pmidlookup?view=long&pmid=15772423 publisherName HighWire Press title Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. mimNumber 602447 referenceNumber 1 publisherAbbreviation HighWire pubmedID 15772423 source J. Lipid Res. 46: 1239-1247, 2005. authors Draganov, D. I., Teiber, J. F., Speelman, A., Osawa, Y., Sunahara, R., La Du, B. N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9329371 publisherName HighWire Press title Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus. mimNumber 602447 referenceNumber 2 publisherAbbreviation HighWire pubmedID 9329371 source J. Clin. Endocr. Metab. 82: 3373-3377, 1997. authors Hegele, R. A., Connelly, P. W., Scherer, S. W., Hanley, A. J. G., Harris, S. B., Tsui, L.-C., Zinman, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0193-73 publisherName Nature Publishing Group title The molecular basis of the human serum paraoxonase activity polymorphism. mimNumber 602447 referenceNumber 3 publisherAbbreviation NPG pubmedID 8098250 source Nature Genet. 3: 73-76, 1993. authors Humbert, R., Adler, D. A., Disteche, C. M., Hassett, C., Omiecinski, C. J., Furlong, C. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1046-5928(05)00258-5 publisherName Elsevier Science title Cloning, purification, and refolding of human paraoxonase-3 expressed in Escherichia coli and its characterization. mimNumber 602447 referenceNumber 4 publisherAbbreviation ES pubmedID 16139510 source Protein Expression and Purification 46: 92-99, 2006. authors Lu, H., Zhu, J., Zang, Y., Ze, Y., Qin, J. pubmedImages false publisherUrl http://www.elsevier.com/ title Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. mimNumber 602447 referenceNumber 5 pubmedID 9714608 source Gene 213: 149-157, 1998. authors Mochizuki, H., Scherer, S. W., Xi, T., Nickle, D. C., Majer, M., Huizenga, J. J., Tsui, L.-C., Prochazka, M. pubmedImages false source Am. J. Hum. Genet. 59 (suppl.): A406, 1996. mimNumber 602447 authors Primo-Parmo, S. L., Hsu, C., Law, D. J., La Du, B. N. title Location and arrangement of three paraoxonase genes: PON1, PON2, and PON3, on human chromosome 7. (Abstract) referenceNumber 6 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888754396902256 publisherName Elsevier Science title The human serum paraoxonase/arylesterase gene (PON1) is one member of multigene family. mimNumber 602447 referenceNumber 7 publisherAbbreviation ES pubmedID 8661009 source Genomics 33: 498-507, 1996. authors Primo-Parmo, S. L., Sorenson, R. C., Teiber, L., La Du, B. N. pubmedImages false publisherUrl http://www.elsevier.com/ source Diabetes 44 (suppl.): 42A, 1995. mimNumber 602447 authors Prochazka, M., Thompson, D. B., Scherer, S. W., Tsui, L.-C., Knowler, W. C., Bennett, P. H., Bogardus, C. title Linkage and association of insulin resistance and NIDDM with markers at 7q21.3-q22.1 in the Pima Indians. (Abstract) referenceNumber 8 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60120-7 publisherName Elsevier Science title DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. mimNumber 602447 referenceNumber 9 publisherAbbreviation ES pubmedID 9443862 source Am. J. Hum. Genet. 62: 36-44, 1998. authors Sanghera, D. K., Aston, C. E., Saha, N., Kamboh, M. I. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks mgiIDs MGI:106687 cmgGene false mgiHumanDisease false ncbiReferenceSequences 530386127,66529395,66529293,530386129,530386131 refSeqAccessionIDs NG_008725.1 dermAtlas false hprdIDs 03903 swissProtIDs Q15165 zfinIDs ZDB-GENE-030131-7116 uniGenes Hs.744912 gtr false wormbaseIDs WBGene00138653,WBGene00118847,WBGene00140888,WBGene00056635,WBGene00033068,WBGene00118848,WBGene00033067,WBGene00118849,WBGene00090844,WBGene00077701,WBGene00003170,WBGene00010775,WBGene00031865,WBGene00044697,WBGene00062344,WBGene00017089,WBGene00062343,WBGene00153067,WBGene00096103 ensemblIDs ENSG00000105854,ENST00000222572 umlsIDs C1418755 genbankNucleotideSequences 2228774,194376209,148146385,2228776,164694011,25058932,511811562,1333631,3947441,2182127,28279806,30217214,194382083,62205248,27658001,158255641,3694657,194383759,74230038,34189330,51094869,58737022,164694222 geneTests false approvedGeneSymbols PON2 geneIDs 5445 proteinSequences 66529396,2228775,194383760,194376210,2228777,530386128,530386130,28279807,2182128,119597169,119597170,194382084,119597171,119597172,1333632,119597173,34189331,189054815,55249558,51094886,27658002,158255642,66529294,3694659,325511384,58737023 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 1022050800 geneMap geneSymbols LCAT sequenceID 11243 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 606967 phenotypeInheritance Autosomal recessive phenotype Fish-eye disease phenotypeMimNumber 136120 phenotypeMappingKey 3 mimNumber 606967 phenotypeInheritance Autosomal recessive phenotype Norum disease phenotypeMimNumber 245900 chromosomeLocationStart 67973786 chromosomeSort 460 chromosomeSymbol 16 mimNumber 606967 geneInheritance None confidence C mappingMethod F, LD, A, REa geneName Lecithin-cholesterol acyltransferase comments very close to HP mouseMgiID MGI:96755 mouseGeneSymbol Lcat computedCytoLocation 16q22.1 cytoLocation 16q22.1 transcript uc002euy.1 chromosomeLocationEnd 67978655 chromosome 16 contributors Victor A. McKusick - updated : 8/24/2006 externalLinks mgiIDs MGI:96755 mgiHumanDisease false nextGxDx true ncbiReferenceSequences 530423913,4557891 refSeqAccessionIDs NG_009778.1 dermAtlas false hprdIDs 06098 swissProtIDs P04180 zfinIDs ZDB-GENE-010716-3 uniGenes Hs.387239 gtr true cmgGene false ensemblIDs ENSG00000213398,ENST00000264005 umlsIDs C1416804 genbankNucleotideSequences 511793125,4731404,37790793,71516170,32879838,187022,34284,34286,187026,187024,241428,148166696,29336195,15928622 geneTests true approvedGeneSymbols LCAT geneIDs 3931 proteinSequences 4557892,4731405,125993,307117,37790794,32879839,5931728,119603596,386858,34287,187025,241429,15928623 geneticsHomeReferenceIDs gene;;LCAT;;LCAT clinicalSynopsisExists false mimNumber 606967 allelicVariantList allelicVariant status live name LCAT DEFICIENCY dbSnps rs267607211 text In the Italian patient with familial LCAT deficiency ({245900}) reported by {25:Vergani et al. (1983)}, {23:Taramelli et al. (1990)} found a C-to-T transition in the fourth exon of the LCAT gene resulting in a substitution of arginine for tryptophan at position 147 of the mature protein. The functional significance of the substitution with respect to the enzyme defect was demonstrated by transfection of the mutated gene into COS-1 cells. The patient appeared to be a compound heterozygote. The nature of the second mutation was not determined. mutations LCAT, TRP147ARG number 1 clinvarAccessions RCV000003841;;1 status live name LCAT DEFICIENCY dbSnps rs121908048 text In a 56-year-old Japanese male with familial LCAT deficiency ({245900}) manifested by corneal opacity since childhood and normocytic normochromic anemia, {15:Maeda et al. (1991)} demonstrated a G-to-A transition in exon 6 leading to substitution of isoleucine for methionine at residue 293 of the mature enzyme. The parents were first cousins, and a sister was similarly affected. Both sibs were homozygous for the mutation. mutations LCAT, MET293ILE number 2 clinvarAccessions RCV000003842;;1 status live name LCAT DEFICIENCY text In a Japanese patient with LCAT deficiency ({245900}), {6:Gotoda et al. (1991)} found a 3-bp insertion in exon 4. This would be expected to cause a substantial change in the enzyme structure. The patient showed severe renal insufficiency. The 3-bp insertion introduced a glycine residue in the middle of an alpha-helical region in exon 4. Glycine has structural flexibility that is disadvantageous in the maintenance of higher protein structures. Thus, the insertion of a single glycine residue could cause alteration in the enzyme conformation that could destabilize and inactivate the LCAT molecule. mutations LCAT, 3-BP INS number 3 clinvarAccessions RCV000003843;;1 status live name LCAT DEFICIENCY dbSnps rs121908049 text In a patient with LCAT deficiency ({245900}), {6:Gotoda et al. (1991)} described a replacement of asparagine-228 with positively charged lysine. The mutation completely abolished enzyme activity and was associated with massive proteinuria. By way of contrast, the conservative amino acid substitution met293ile gave rise to only a partially defective enzyme, and the patient studied had no proteinuria despite the presence of corneal opacities and anemia. mutations LCAT, ASN228LYS number 4 clinvarAccessions RCV000003844;;1 status live name FISH-EYE DISEASE dbSnps rs121908050 text {4:Funke et al. (1991)} described the biochemical and genetic presentation of 2 homozygotes from a German family with fish-eye disease ({136120}) and their relatives. They demonstrated vertical transmission of a decrease in the specific activity of LCAT. Two brothers, 57 and 68 years old, had massive bilateral corneal opacities that almost completely covered the irides. There were several consanguineous marriages in their family history. In their village, the kindred was known to have been affected with 'sick eyes' for several generations. The younger brother suffered from angiographically assessed 2-vessel coronary disease. The elder brother suffered from angina pectoris. Family history, however, was not compatible with an increased prevalence of myocardial infarction. All 5 children of the 2 presumed homozygotes were heterozygotes. Direct sequencing of DNA segments of the LCAT gene amplified by PCR led to the identification of a homozygous mutation resulting in the substitution of threonine for isoleucine at codon 123. The change was from ACA to ATA. Homozygosity for precisely the same mutation was identified in an unrelated Dutch family. mutations LCAT, ILE123THR number 5 clinvarAccessions RCV000003845;;1 status live name LCAT DEFICIENCY text In a Japanese case of LCAT deficiency ({245900}) in which both LCAT mass and activity were nearly absent, Southern blot hybridization showed no gross rearrangement of the gene ({2:Bujo et al., 1991}). Sequence analysis, however, demonstrated an extra nucleotide C insertion in the first exon. This single base insertion caused a shift of the following reading frame and resulted in a truncated LCAT polypeptide consisting of only 16 amino acids. The proband, aged 28 years, was homozygous for the mutant allele. She suffered from massive corneal opacifications, anemia, proteinuria, and decreased plasma concentrations of esterified cholesterol, apoA-I, and apoA-II, in addition to the absent LCAT mass and activity. In her parents, 1 sister, and 1 son, both LCAT mass and activity were about one-half normal. {2:Bujo et al. (1991)} commented on the loss of LCAT activity on HDL particle (alpha-LCAT activity) in fish-eye disease, whereas total LCAT activity is lost in what is generally called LCAT deficiency (Norum disease). mutations LCAT, 1-BP INS, EX1 number 6 clinvarAccessions RCV000003846;;1 status live name FISH-EYE DISEASE dbSnps rs121908051 text {22:Skretting and Prydz (1992)} amplified the LCAT gene in DNA samples from 2 of the original Swedish fish-eye disease ({136120}) patients and sequenced the exons by the dideoxy method. The 2 patients, although apparently unrelated, showed the same mutation in codon 10 of the first exon, altering proline-10 to leucine. mutations LCAT, PRO10LEU number 7 clinvarAccessions RCV000003847;;1 status live name FISH-EYE DISEASE dbSnps rs121908050 text In a 66-year-old patient with fish-eye disease ({136120}), {10:Klein et al. (1992)} found compound heterozygosity for a thr123-to-ile mutation and a thr347-to-met mutation. mutations LCAT, THR123ILE number 8 clinvarAccessions RCV000003845;;1 status live name FISH-EYE DISEASE dbSnps rs121908053 text See {606967.0008} and {10:Klein et al. (1992)}. mutations LCAT, THR347MET number 9 clinvarAccessions RCV000003849;;1 status live name LCAT DEFICIENCY dbSnps rs121908054 text In studies of 3 of the original Norwegian LCAT deficiency ({245900}) families ({18:Norum and Gjone, 1967}), {21:Skretting et al. (1992)} found a T-to-A transversion in codon 252 in exon 6 converting met (ATG) to lys (AAG) in all homozygotes. In spite of the identical mutation, the clinical picture differed in severity. This variation in severity was not reflected in the expression of LCAT in the heterozygotes. mutations LCAT, MET252LYS number 10 clinvarAccessions RCV000003850;;1 status live name LCAT DEFICIENCY dbSnps rs28942087 text In 6 probands from 5 families originating from 4 different countries, {5:Funke et al. (1993)} confirmed the diagnosis of LCAT deficiency ({245900}) by the absence or near absence of LCAT activity. Also, all probands showed other invariant symptoms of LCAT deficiency as well as a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal. In the probands of 2 families, no mass was detectable, while in other probands reduced amounts of LCAT mass indicated the presence of a functionally inactive protein. Sequence analysis identified homozygous missense or nonsense mutations in the probands of 4 families. In a fifth family, 2 probands were found to be compound heterozygotes for a missense mutation and for a single-base insertion causing a reading frameshift. The molecular defects were dispersed in different regions of the enzyme, suggesting the existence of several functionally important structural domains in this enzyme. In their family A, from France, {5:Funke et al. (1993)} found a CTT-to-CCT transition resulting in substitution of proline for leucine-209. mutations LCAT, LEU209PRO number 11 clinvarAccessions RCV000003851;;1 status live name LCAT DEFICIENCY dbSnps rs28940886,rs387906300 text In their family B, from Denmark, {5:Funke et al. (1993)} found homozygosity for a double mutation in the LCAT gene: ala93thr and arg158cys. These amino acid substitutions resulted, respectively, from GCC-to-ACC and CGC-to-TGC transitions. mutations LCAT, ALA93THR AND ARG158CYS number 12 clinvarAccessions RCV000003852;;1 status live name LCAT DEFICIENCY dbSnps rs28940887 text In their family C, from Canada, {5:Funke et al. (1993)} found that both affected persons were compound heterozygotes. One allele carried a CGG-to-TGG transition converting arg135 to trp. The other allele carried an insertion of an adenine between codons 375 and 376, converting codon 376 from glutamine to threonine and causing a frameshift with premature termination at codon 416 ({606967.0014}). mutations LCAT, ARG135TRP number 13 clinvarAccessions RCV000003853;;1 status live name LCAT DEFICIENCY text See {606967.0013} for a description of the second mutation in family C of {5:Funke et al. (1993)}. mutations LCAT, 1-BP INS, GLN376THR, FS number 14 clinvarAccessions RCV000003854;;1 status live name LCAT DEFICIENCY dbSnps rs28940888 text In their family D, from Italy, {5:Funke et al. (1993)} identified homozygosity for an ACG-to-ATG transition converting codon 321 from threonine to methionine. mutations LCAT, THR321MET number 15 clinvarAccessions RCV000003855;;1 status live name LCAT DEFICIENCY dbSnps rs121908055 text In their family E, from Italy, {5:Funke et al. (1993)} found homozygosity for a TAC-to-TAA transversion converting tyrosine-83 to a stop codon. mutations LCAT, TYR83TER number 16 clinvarAccessions RCV000003856;;1 status live name FISH-EYE DISEASE dbSnps rs121908056 text {11:Klein et al. (1993)} demonstrated that 2 sibs with fish-eye disease ({136120}) were homozygous for deletion of the triplet coding for leucine-300. The classic clinical and biochemical features demonstrated by the sibs included corneal opacities, HDL cholesterol less than 10 mg/dl, normal plasma cholesteryl esters, and elevated triglycerides. The deletion of leucine-300 was accompanied by loss of a restriction site for MlnI. Expression of the mutant LCAT gene in human embryonic kidney cells revealed normal mRNA and intracellular LCAT concentrations. However, reduced amounts of the mutant protein, which had a normal specific alpha-LCAT activity, were present in the medium. This was the first report of fish-eye disease associated with a mutant enzyme that had a normal alpha-LCAT-specific activity. {11:Klein et al. (1993)} proposed that the residual amount of total plasma LCAT activity and not its distribution on lipoproteins primarily determines the heterogeneity in phenotypic expression observed in familial LCAT deficiency ({245900}) syndromes. mutations LCAT, LEU300DEL number 17 clinvarAccessions RCV000003857;;1 status live name FISH-EYE DISEASE dbSnps rs121908057 text {13:Kuivenhoven et al. (1995)} found an asn131-to-asp (N131D) substitution in the LCAT gene in homozygous state in 2 brothers and 2 sisters with fish-eye disease ({136120}) from a sibship of 11 and in heterozygous state in 34 other members of the kindred. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a nearly complete absence of LCAT activity. Heterozygotes showed a highly significant reduction of HDL-cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant mutant LCAT against proteoliposomes. Unlike other mutations causing fish-eye disease, the recombinant LCAT also showed a 75% reduction in specific activity against LDL. {13:Kuivenhoven et al. (1995)} stated that these unique biochemical characteristics revealed the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and a specific loss of activity against HDL. The authors speculated that the impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the 2 male probands. mutations LCAT, ASN131ASP number 18 clinvarAccessions RCV000003858;;1 status live name FISH-EYE DISEASE text In a 52-year-old Dutch female and 2 younger sisters with bilateral clouding of the cornea as the only clinical abnormality and no premature atherosclerosis (see {136120}), {14:Kuivenhoven et al. (1996)} described a point mutation in the lariat branchpoint sequence of the LCAT gene. The first step in the splicing of an intron from nuclear precursors of mRNA results in the formation of a lariat structure. A distinct intronic nucleotide sequence, known as the branchpoint region, plays a central role in this process. Sequencing of the LCAT gene of all 3 probands revealed compound heterozygosity for a missense mutation in exon 4, thr123 to ile ({606967.0008}), and a point mutation located in intron 4. The intronic mutation consisted of a T-to-C substitution at position 2327 in intron 4, 22 bases upstream of the acceptor splicing site. mutations LCAT, IVS4AS, T-C, -22 number 19 clinvarAccessions RCV000003859;;1 prefix * titles preferredTitle LECITHIN:CHOLESTEROL ACYLTRANSFERASE; LCAT textSectionList textSection textSectionTitle Description textSectionContent Lecithin:cholesterol acyltransferase (LCAT; {EC 2.3.1.43}) is a soluble enzyme that converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high density lipoproteins ({8:Jonas, 2000}). textSectionName description textSectionTitle Cloning textSectionContent {16:McLean et al. (1986)} cloned the LCAT gene and found that it encodes a 416-amino acid protein with a hydrophobic leader sequence of 24 amino acids. An unusual feature of the message is that the poly(A) signal appears to overlap the COOH-terminal glutamic acid and stop codons. The protein has several extended sequences of hydrophobic amino acids, one of which is similar to sequences in pancreatic lipase and lingual lipase. textSectionName cloning textSectionTitle Gene Structure textSectionContent {16:McLean et al. (1986)} sequenced the LCAT gene and found that it contains 6 exons and spans approximately 4,200 basepairs. textSectionName geneStructure textSectionTitle Mapping textSectionContent {1:Azoulay et al. (1987)} used a cDNA clone corresponding to LCAT to assign the locus to 16q22 through the analysis of DNA from somatic cell hybrids and in situ hybridization. In the mouse the Lcat locus is located on chromosome 8 along with a number of other loci that are found on human chromosome 16q ({20:Scherer et al., 1989}). textSectionName mapping textSectionTitle Gene Function textSectionContent LCAT plays an important role in lipoprotein metabolism, especially in the process termed 'reverse cholesterol transport.' The enzyme is synthesized in the liver and circulates in blood plasma as a complex with components of high density lipoprotein (HDL). Cholesterol from peripheral cells is transferred to HDL particles, esterified through the action of LCAT on HDL, and incorporated into the core of the lipoprotein. The cholesterol ester is thereby transported to the liver ({8:Jonas, 2000}). A lack of LCAT activity would be expected to lead to accumulation of free cholesterol in the tissues. Most cholesterol esters present in plasma are the product of the reaction catalyzed by LCAT in which cholesterol is esterified with the sn-2 fatty acid of phosphatidylcholine. The resulting cholesteryl esters are packed into the hydrophobic core of lipoproteins. In fish-eye disease ({136120}), there is a specific inability of LCAT to esterify cholesterol in HDL, a deficiency of alpha-LCAT function. In Norum disease ({245900}), the deficient esterification is generalized ({9:Kinoshita and Teramoto, 2001}). textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {7:Humphries et al. (1988)} used an LCAT cDNA clone to study the structure of the gene in patients with familial LCAT deficiency ({245900}). Enzymatic digestion of DNA samples from the patients produced LCAT gene fragments which were indistinguishable from those found in normal individuals, thus excluding large deletion or rearrangement of the gene. In the Italian patient with familial LCAT deficiency reported by {25:Vergani et al. (1983)}, {23:Taramelli et al. (1990)} found a C-to-T transition in the fourth exon of the LCAT gene ({606967.0001}), resulting in a substitution of arginine for tryptophan at position 147 of the mature protein. Multiple mutations in the LCAT gene have been described in patients with LCAT deficiency and fish-eye disease ({136120}). {14:Kuivenhoven et al. (1996)} described a point mutation in the lariat branchpoint sequence of the LCAT gene in 3 sisters with fish-eye disease ({606967.0019}). The branchpoint sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders. {12:Kralovicova et al. (2006)} examined the splicing pattern of 9 reporter pre-mRNAs that had been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. One of these was LCAT. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3-prime splice sites and also activated a cryptic 5-prime splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonic transcripts was lower for BP transitions than for BP transversions. Their results improved prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggested that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing. textSectionName molecularGenetics geneMapExists true editHistory terry : 07/06/2012 alopez : 9/6/2006 terry : 8/24/2006 ckniffin : 5/29/2002 carol : 5/28/2002 ckniffin : 5/28/2002 ckniffin : 5/28/2002 dateCreated Wed, 22 May 2002 03:00:00 EDT creationDate Cassandra L. Kniffin : 5/22/2002 epochUpdated 1341558000 dateUpdated Fri, 06 Jul 2012 03:00:00 EDT referenceList reference title The structural gene for lecithin:cholesterol acyl transferase (LCAT) maps to 16q22. mimNumber 606967 referenceNumber 1 pubmedID 3674753 source Ann. Hum. Genet. 51: 129-136, 1987. authors Azoulay, M., Henry, I., Tata, F., Weil, D., Grzeschik, K. H., Chaves, E., McIntyre, N., Williamson, R., Humphries, S. E., Junien, C. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(91)92026-G publisherName Elsevier Science title Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease. mimNumber 606967 referenceNumber 2 publisherAbbreviation ES pubmedID 1662503 source Biochem. Biophys. Res. Commun. 181: 933-940, 1991. authors Bujo, H., Kusunoki, J., Ogasawara, M., Yamamoto, T., Ohta, Y., Shimada, T., Saito, Y., Yoshida, S. pubmedImages false publisherUrl http://www.elsevier.com/ title Lecithin:cholesterol acyl transferase (LCAT). mimNumber 606967 referenceNumber 3 pubmedID 6762928 source Clin. Biochem. 15: 269-278, 1982. authors Frohlich, J., McLeod, R., Hon, K. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2052566 publisherName HighWire Press title A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. mimNumber 606967 referenceNumber 4 publisherAbbreviation HighWire pubmedID 2052566 source Proc. Nat. Acad. Sci. 88: 4855-4859, 1991. authors Funke, H., von Eckardstein, A., Pritchard, P. H., Albers, J. J., Kastelein, J. J. P., Droste, C., Assmann, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI116248 publisherName Journal of Clinical Investigation title Genetic and phenotypic heterogeneity in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: six newly identified defective alleles further contribute to the structural heterogeneity in this disease. mimNumber 606967 referenceNumber 5 publisherAbbreviation JCI pubmedID 8432868 source J. Clin. Invest. 91: 677-683, 1993. authors Funke, H., von Eckardstein, A., Pritchard, P. H., Hornby, A. E., Wiebusch, H., Motti, C., Hayden, M. R., Dachet, C., Jacotot, B., Gerdes, U., Faergeman, O., Albers, J. J., Colleoni, N., Catapano, A., Frohlich, J., Assmann, G. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(91)90665-C publisherName Elsevier Science title Differential phenotypic expression by three mutant alleles in familial lecithin:cholesterol acyltransferase deficiency. mimNumber 606967 referenceNumber 6 publisherAbbreviation ES pubmedID 1681161 source Lancet 338: 778-781, 1991. authors Gotoda, T., Yamada, N., Murase, T., Sakuma, M., Murayama, N., Shimano, H., Kozaki, K., Albers, J. J., Yazaki, Y., Akanuma, Y. pubmedImages false publisherUrl http://www.elsevier.com/ title A study of the structure of the gene for lecithin:cholesterol acyltransferase in four unrelated individuals with familial lecithin:cholesterol acyltransferase deficiency. mimNumber 606967 referenceNumber 7 pubmedID 3338256 source Clin. Sci. 74: 91-96, 1988. authors Humphries, S. E., Chaves, M. E., Tata, F., Lima, V. L. M., Owen, J. S., Borysiewicz, L. K., Catapano, A., Vergani, C., Gjone, E., Clemens, M. R., Williamson, R., McIntyre, N. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1388-1981(00)00153-0 publisherName Elsevier Science title Lecithin cholesterol acyltransferase. mimNumber 606967 referenceNumber 8 publisherAbbreviation ES pubmedID 11111093 source Biochim. Biophys. Acta 1529: 245-256, 2000. authors Jonas, A. pubmedImages false publisherUrl http://www.elsevier.com/ title LCAT (lecithin:cholesterol acyltransferase). mimNumber 606967 referenceNumber 9 pubmedID 11797372 source Rinsho Byori Suppl. 116: 125-130, 2001. authors Kinoshita, M., Teramoto, T. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI115612 publisherName Journal of Clinical Investigation title Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome: lecithin-cholesterol acyltransferase (thr123-to-ile) and lecithin-cholesterol acyltransferase (thr347-to-met). mimNumber 606967 referenceNumber 10 publisherAbbreviation JCI pubmedID 1737840 source J. Clin. Invest. 89: 499-506, 1992. authors Klein, H.-G., Lohse, P., Pritchard, P. H., Bojanovski, D., Schmidt, H., Brewer, H. B., Jr. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI116591 publisherName Journal of Clinical Investigation title Fish eye syndrome: a molecular defect in the lecithin-cholesterol acyltransferase (LCAT) gene associated with normal alpha-LCAT-specific activity: implications for classification and prognosis. mimNumber 606967 referenceNumber 11 publisherAbbreviation JCI pubmedID 8326012 source J. Clin. Invest. 92: 479-485, 1993. authors Klein, H.-G., Santamarina-Fojo, S., Duverger, N., Clerc, M., Dumon, M.-F., Albers, J. J., Marcovina, S., Brewer, H. B., Jr. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1002/humu.20362 publisherName John Wiley & Sons, Inc. title Phenotypic consequences of branch point substitutions. mimNumber 606967 referenceNumber 12 publisherAbbreviation Wiley pubmedID 16835862 source Hum. Mutat. 27: 803-813, 2006. authors Kralovicova, J., Lei, H., Vorechovsky, I. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1172/JCI118348 publisherName Journal of Clinical Investigation title A unique genetic and biochemical presentation of fish-eye disease. mimNumber 606967 referenceNumber 13 publisherAbbreviation JCI pubmedID 8675648 source J. Clin. Invest. 96: 2783-2791, 1995. authors Kuivenhoven, J. A., van Voorst tot Voorst, E. J. G. M., Wiebusch, H., Marcovina, S. M., Funke, H., Assmann, G., Pritchard, P. H., Kastelein, J. J. P., Hill, J., Adler, L., Errami, A. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI118800 publisherName Journal of Clinical Investigation title An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease). mimNumber 606967 referenceNumber 14 publisherAbbreviation JCI pubmedID 8755645 source J. Clin. Invest. 98: 358-364, 1996. authors Kuivenhoven, J. A., Weibusch, H., Pritchard, P. H., Funke, H., Benne, R., Assmann, G., Kastelein, J. J. P. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(91)90129-U publisherName Elsevier Science title Lecithin-cholesterol acyltransferase (LCAT) deficiency with a missense mutation in exon 6 of the LCAT gene. mimNumber 606967 referenceNumber 15 publisherAbbreviation ES pubmedID 1859405 source Biochem. Biophys. Res. Commun. 178: 460-466, 1991. authors Maeda, E., Naka, Y., Matozaki, T., Sakuma, M., Akanuma, Y., Yoshino, G., Kasuga, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=3458198 publisherName HighWire Press title Cloning and expression of human lecithin-cholesterol acyltransferase cDNA. mimNumber 606967 referenceNumber 16 publisherAbbreviation HighWire pubmedID 3458198 source Proc. Nat. Acad. Sci. 83: 2335-2339, 1986. authors McLean, J., Fielding, C., Drayna, D., Dieplinger, H., Baer, B., Kohr, W., Henzel, W., Lawn, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3797244 publisherName HighWire Press title Human lecithin-cholesterol acyltransferase gene: complete gene sequence and sites of expression. mimNumber 606967 referenceNumber 17 publisherAbbreviation HighWire pubmedID 3797244 source Nucleic Acids Res. 14: 9397-9406, 1986. authors McLean, J., Wion, K., Drayna, D., Fielding, C., Lawn, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0005-2760(67)90064-1 publisherName Elsevier Science title Familial serum-cholesterol esterification failure: a new inborn error of metabolism. mimNumber 606967 referenceNumber 18 publisherAbbreviation ES pubmedID 6078131 source Biochim. Biophys. Acta 144: 698-700, 1967. authors Norum, K. R., Gjone, E. pubmedImages false publisherUrl http://www.elsevier.com/ title Lecithin:cholesterol acyltransferase: recent research in biochemistry and physiology of the enzyme. mimNumber 606967 referenceNumber 19 pubmedID 4604673 source Scand. J. Clin. Lab. Invest. 33: 191-197, 1974. authors Norum, K. R., Gjone, E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0888-7543(89)90058-X publisherName Elsevier Science title Gene mapping on mouse chromosome 8 by interspecific crosses: new data on a linkage group conserved on human chromosome 16q. mimNumber 606967 referenceNumber 20 publisherAbbreviation ES pubmedID 2571576 source Genomics 5: 275-282, 1989. authors Scherer, G., Bausch, E., Gaa, A., von Deimling, O. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0014-5793(92)80795-I publisherName Elsevier Science title The genetic defect of the original Norwegian lecithin:cholesterol acyltransferase deficiency families. mimNumber 606967 referenceNumber 21 publisherAbbreviation ES pubmedID 1516702 source FEBS Lett. 309: 307-310, 1992. authors Skretting, G., Blomhoff, J. P., Solheim, J., Prydz, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(92)91772-I publisherName Elsevier Science title An amino acid exchange in exon I of the human lecithin:cholesterol acyltransferase (LCAT) gene is associated with fish eye disease. mimNumber 606967 referenceNumber 22 publisherAbbreviation ES pubmedID 1571050 source Biochem. Biophys. Res. Commun. 182: 583-587, 1992. Note: Erratum: Biochem. Biophys. Res. Commun. 184: 549 only, 1992. authors Skretting, G., Prydz, H. pubmedImages false publisherUrl http://www.elsevier.com/ title Lecithin cholesterol acyl transferase deficiency: molecular analysis of a mutated allele. mimNumber 606967 referenceNumber 23 pubmedID 2370048 source Hum. Genet. 85: 195-199, 1990. authors Taramelli, R., Pontoglio, M., Candiani, G., Ottolenghi, S., Dieplinger, H., Catapano, A., Albers, J., Vergani, C., McLean, J. pubmedImages false title Genetics of LCAT (lecithin:cholesterol acyltransferase) deficiency. mimNumber 606967 referenceNumber 24 pubmedID 806250 source Ann. Hum. Genet. 38: 327-331, 1975. authors Teisberg, P., Gjone, E., Olaisen, B. pubmedImages false title A new case of familial LCAT deficiency. mimNumber 606967 referenceNumber 25 pubmedID 6624548 source Acta Med. Scand. 214: 173-176, 1983. authors Vergani, C., Catapano, A. L., Roma, P., Giudici, G. pubmedImages false seeAlso Frohlich et al. (1982); McLean et al. (1986); Norum and Gjone (1974); Teisberg et al. (1975)

entryList

entry status live phenotypeMapList phenotypeMap geneSymbols CBS sequenceID 13948 chromosomeLocationStart 44473300 chromosomeSort 121 phenotypeMimNumber 236200 chromosomeSymbol 21 mimNumber 613381 geneInheritance None phenotypeInheritance Autosomal recessive phenotypeMappingKey 3 phenotype Thrombosis, hyperhomocysteinemic computedCytoLocation 21q22.3 cytoLocation 21q22.3 transcript uc002zcv.2 chromosomeLocationEnd 44496471 chromosome 21 geneSymbols CBS sequenceID 13948 chromosomeLocationStart 44473300 chromosomeSort 121 phenotypeMimNumber 236200 chromosomeSymbol 21 mimNumber 613381 geneInheritance None phenotypeInheritance Autosomal recessive phenotypeMappingKey 3 phenotype Homocystinuria, B6-responsive and nonresponsive types computedCytoLocation 21q22.3 cytoLocation 21q22.3 transcript uc002zcv.2 chromosomeLocationEnd 44496471 chromosome 21 contributors Cassandra L. Kniffin - updated : 10/11/2010 Cassandra L. Kniffin - reorganized : 5/4/2010 Cassandra L. Kniffin - updated : 4/28/2010 Cassandra L. Kniffin - updated : 9/3/2009 George E. Tiller - updated : 11/20/2008 Cassandra L. Kniffin - updated : 5/24/2006 Cassandra L. Kniffin - updated : 2/17/2006 Victor A. McKusick - updated : 2/10/2004 Victor A. McKusick - updated : 1/12/2004 Ada Hamosh - updated : 10/8/2003 Ada Hamosh - updated : 10/6/2003 Victor A. McKusick - updated : 8/20/2002 Victor A. McKusick - updated : 6/14/2002 Victor A. McKusick - updated : 2/8/2002 Ada Hamosh - updated : 1/16/2002 Victor A. McKusick - updated : 1/10/2002 Victor A. McKusick - updated : 9/7/2001 Victor A. McKusick - updated : 6/27/2001 Carol A. Bocchini - updated : 6/27/2001 George E. Tiller - updated : 5/29/2001 Victor A. McKusick - updated : 5/15/2001 Paul J. Converse - updated : 6/8/2000 Victor A. McKusick - updated : 12/21/1999 Victor A. McKusick - updated : 6/30/1999 Victor A. McKusick - updated : 6/18/1999 Victor A. McKusick - updated : 6/7/1999 Victor A. McKusick - updated : 5/14/1999 Ada Hamosh - updated : 4/21/1999 Victor A. McKusick - updated : 2/25/1999 Victor A. McKusick - updated : 2/3/1999 Victor A. McKusick - updated : 12/2/1998 Ada Hamosh - updated : 10/26/1998 Victor A. McKusick - updated : 9/17/1998 John F. Jackson - reorganized : 9/2/1998 Victor A. McKusick - updated : 4/28/1998 Victor A. McKusick - updated : 4/15/1998 Victor A. McKusick - updated : 2/25/1998 Victor A. McKusick - updated : 2/17/1998 Victor A. McKusick - updated : 2/12/1998 Victor A. McKusick - updated : 1/29/1998 Victor A. McKusick - updated : 12/19/1997 Victor A. McKusick - updated : 6/5/1997 Victor A. McKusick - updated : 4/24/1997 Victor A. McKusick - updated : 4/4/1997 Victor A. McKusick - updated : 2/28/1997 Moyra Smith - updated : 5/21/1996 externalLinks wormbaseIDs WBGene00140875,WBGene00007653,WBGene00132241,WBGene00024287,WBGene00010759,WBGene00104153,WBGene00125647,WBGene00122633,WBGene00031822,WBGene00144789,WBGene00013866,WBGene00019962,WBGene00018783,WBGene00063155,WBGene00042990,WBGene00161805,WBGene00025115,WBGene00067605,WBGene00019096,WBGene00072084 cmgGene false mgiHumanDisease true nextGxDx false hprdIDs 01994 coriellDiseases HOM23620;;HOMOCYSTINURIA nbkIDs NBK1524;;Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency dermAtlas false swissProtIDs P35520 possumSyndromes 3253;;Homocystinuria orphanetDiseases 394;;173;;Classical homocystinuria gtr true ordrDiseases 6667;;Homocystinuria due to CBS deficiency umlsIDs C1439329,C3150344 geneTests false geneticAllianceIDs 3462 newbornScreeningUrls true geneticsHomeReferenceIDs condition;;homocystinuria;;homocystinuria locusSpecificDBs http://www.uchsc.edu/cbs/;;Cystathionine beta-synthase database clinicalSynopsisExists true mimNumber 236200 dateCreated Tue, 03 Jun 1986 03:00:00 EDT clinicalSynopsis skinNailsHairSkinHistologyExists false headAndNeckEyesExists true headAndNeckMouthExists true genitourinaryBladderExists false skeletalSkullExists false genitourinaryExists false neurologicBehavioralPsychiatricManifestationsExists true molecularBasisExists true genitourinaryUretersExists false hematologyExists true creationDate John F. Jackson : 6/15/1995 prenatalManifestationsExists false headAndNeckMouth High-arched palate {SNOMEDCT:27272007} {ICD10CM:Q38.5} {UMLS:C0240635} {HPO HP:0000218 UMLS:C0240635,C1398297} cardiovascularHeartExists true hematology Thromboembolism (25%) {UMLS:C3550383} {HPO HP:0001907 UMLS:C0040038} dateCreated Thu, 15 Jun 1995 03:00:00 EDT cardiovascularExists true respiratoryExists false prenatalManifestationsPlacentaAndUmbilicalCordExists false dateUpdated Tue, 17 Jul 2012 03:00:00 EDT skeletalSpineExists true chestRibsSternumClaviclesAndScapulaeExists true abdomenPancreasExists true skeletal Generalized osteoporosis {UMLS:C1850194} {HPO HP:0000939 UMLS:C0029456} chestRibsSternumClaviclesAndScapulae Pectus excavatum {SNOMEDCT:391987005} {UMLS:C2051831} {HPO HP:0000767 UMLS:C0016842}; Pectus carinatum {SNOMEDCT:38774000} {UMLS:C2939416} {HPO HP:0000768 UMLS:C2939416} inheritanceExists true molecularBasis Caused by mutation in the cystathionine beta-synthase gene (CBS, {613381.0001}) abdomenBiliaryTractExists false prenatalManifestationsMovementExists false skeletalHandsExists false growthWeightExists false growthHeightExists true skinNailsHairHairExists true genitourinaryInternalGenitaliaFemaleExists false headAndNeckHeadExists false prenatalManifestationsDeliveryExists false oldFormatExists false prenatalManifestationsAmnioticFluidExists false cardiovascularVascularExists false genitourinaryKidneysExists false skeletalLimbs Dolichostenomelia {SNOMEDCT:62250003} {UMLS:C0003706} {HPO HP:0001519 UMLS:C0003706,C1836997}; Arachnodactyly {SNOMEDCT:62250003} {UMLS:C0003706} {HPO HP:0001166}; Limited joint mobility {UMLS:C1856088} {HPO HP:0001376 UMLS:C1856088} genitourinaryInternalGenitaliaMaleExists false abdomenLiverExists true headAndNeckFaceExists false chestExists true headAndNeckTeethExists true headAndNeckNeckExists false laboratoryAbnormalities Homocystinuria {SNOMEDCT:11282001} {ICD10CM:E72.11} {UMLS:C0019880} {HPO HP:0002156 UMLS:C1439329}; Methioninuria {UMLS:C1856089}; Cystathionine beta-synthase deficiency {UMLS:C1439329} abdomenPancreas Pancreatitis {UMLS:C1963198} {HPO HP:0001733 UMLS:C0030305} skeletalPelvisExists false growthExists true abdomenGastrointestinalExists false voiceExists false skeletalExists true skeletalLimbsExists true laboratoryAbnormalitiesExists true miscellaneousExists true editHistory joanna : 07/17/2012 ckniffin : 10/11/2010 joanna : 3/14/2005 joanna : 1/18/2000 carol : 12/7/1999 carol : 12/5/1999 abdomenSpleenExists false respiratoryAirwaysExists false growthOther Occasional failure to thrive in infancy {UMLS:C1856086} headAndNeckExists true growthHeight Normal to tall stature {UMLS:C1856085} respiratoryLungExists false abdomenExists true skinNailsHairSkinElectronMicroscopyExists false headAndNeckEyes Ectopia lentis {SNOMEDCT:74969002} {ICD10CM:Q12.1} {ICD9CM:743.37} {UMLS:C0013581} {HPO HP:0001083 UMLS:C0013581,C0023309}; Myopia {SNOMEDCT:57190000} {ICD10CM:H52.1} {ICD9CM:367.1} {UMLS:C0027092} {HPO HP:0000545 UMLS:C0027092}; Glaucoma {UMLS:C1962986} {HPO HP:0000501 UMLS:C1962986} immunologyExists false skeletalFeetExists false headAndNeckEarsExists false respiratoryNasopharynxExists false neurologicPeripheralNervousSystemExists false neoplasiaExists false chestBreastsExists false headAndNeckTeeth Crowded teeth {SNOMEDCT:12351004} {ICD9CM:524.31} {UMLS:C0040433} {HPO HP:0000678 UMLS:C0040433,C1847525} abdomenExternalFeaturesExists true skeletalSpine Biconcave 'codfish' vertebrae {UMLS:C1856087} {HPO HP:0004586 UMLS:C1849077}; Kyphoscoliosis {SNOMEDCT:405771009} {UMLS:C0600033} {HPO HP:0002751 UMLS:C0600033} respiratoryLarynxExists false skinNailsHairSkin Hypopigmentation {UMLS:C1963139} {HPO HP:0001010 UMLS:C1844614,C1876214}; Malar flush {UMLS:C3550384}; Livedo reticularis {SNOMEDCT:238772004} {UMLS:C0085642} {HPO HP:0000965 UMLS:C0263401} contributors Cassandra L. Kniffin - updated : 10/11/2010 Kelly A. Przylepa - revised : 12/5/1999 skinNailsHairExists true chestDiaphragmExists false abdomenLiver Fatty changes in liver {SNOMEDCT:197321007} {UMLS:C0015695} prenatalManifestationsMaternalExists false neurologicCentralNervousSystem Seizures {SNOMEDCT:91175000} {ICD10CM:R56.9} {ICD9CM:780.3} {UMLS:C0036572} {HPO HP:0001250 UMLS:C0036572}; Mental retardation {SNOMEDCT:91138005} {UMLS:C0025362} {HPO HP:0001249 UMLS:C0025362,C0423903}; Cerebrovascular accident {SNOMEDCT:230690007} {ICD10CM:I63.9} {UMLS:C0038454} {HPO HP:0001297 UMLS:C0038454,C1849743} inheritance Autosomal recessive {SNOMEDCT:258211005} {UMLS:C0441748} {HPO HP:0000007} growthOtherExists true skinNailsHairNailsExists false neurologicCentralNervousSystemExists true abdomenExternalFeatures Inguinal hernia {SNOMEDCT:396232000} {ICD10CM:K40,K40.90} {ICD9CM:550} {UMLS:C0019294} {HPO HP:0000023 UMLS:C0019294} genitourinaryExternalGenitaliaMaleExists false cardiovascularHeart Myocardial infarction {UMLS:C3810814} {HPO HP:0001658 UMLS:C0027051}; Mitral valve prolapse {SNOMEDCT:409712001,8074002} {UMLS:C0026267} {HPO HP:0001634} miscellaneous Fifty-percent of individuals responsive to pyridoxine (vitamin B6) {UMLS:C1856091}; Pyridoxine responsive individuals often have milder manifestations than those not responsive {UMLS:C1856092}; Management of homocystinuria includes low methionine, cystine supplemented diet for pyridoxine nonresponders and pyridoxine supplementation for pyridoxine responders {UMLS:C1856093}; Treatment with betaine, especially for pyridoxine nonresponders {UMLS:C3550386}; Thromboembolism is the most common cause of death {UMLS:C3550387}; Frequency between 1 in 58,000 to 1 in 1,000,000 {UMLS:C3550388} neurologicExists true metabolicFeaturesExists false genitourinaryExternalGenitaliaFemaleExists false skinNailsHairSkinExists true neurologicBehavioralPsychiatricManifestations Psychiatric disorders {SNOMEDCT:74732009} {ICD10CM:F99-F99,F99} {UMLS:C0004936} {HPO HP:0000708 UMLS:C1856060}; Depression {UMLS:C1999266} {HPO HP:0000716 UMLS:C0344315}; Personality disorder {SNOMEDCT:33449004} {ICD10CM:F60.9} {ICD9CM:301,301.9} {UMLS:C0031212} {HPO HP:0012075} epochUpdated 1342508400 headAndNeckNoseExists false endocrineFeaturesExists false skinNailsHairHair Hypopigmentation {UMLS:C1963139} {HPO HP:0001010 UMLS:C1844614,C1876214}; Fine, brittle hair {UMLS:C1844619} chestExternalFeaturesExists false muscleSoftTissueExists false epochCreated 803199600 prefix # titles alternativeTitles HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE;; CYSTATHIONINE BETA-SYNTHASE DEFICIENCY;; CBS DEFICIENCY includedTitles HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, INCLUDED preferredTitle HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY phenotypeMapExists true textSectionList textSection textSectionTitle Text textSectionContent A number sign (#) is used with this entry because homocystinuria with or without response to pyridoxine is caused by homozygous or compound heterozygous mutation in the gene encoding cystathionine beta-synthase (CBS; {613381}) on chromosome 21q22. textSectionName text textSectionTitle Description textSectionContent Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome (MFS; {154700}), and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. There are 2 main phenotypes of the classic disorder: a milder pyridoxine (vitamin B6)-responsive form, and a more severe pyridoxine-nonresponsive form. Pyridoxine is a cofactor for the CBS enzyme, and can aid in the conversion of homocysteine to cysteine (summary by {75:Reish et al., 1995} and {88:Testai and Gorelick, 2010}). Some patients have been reported to have a milder form of homocystinuria, which is characterized by increased plasma homocysteine and increased risk for thrombotic events in young adulthood, but without the other skeletal, ocular, or nervous system manifestations observed in classic homocystinuria ({39:Kelly et al., 2003}). textSectionName description textSectionTitle Clinical Features textSectionContent Homocystinuria was discovered independently by {27:Gerritsen et al. (1962)} in Madison, Wisconsin, and by {12:Carson and Neill (1962)} in Belfast, Northern Ireland. The patients of both groups were studied because of mental retardation. {68:Mudd et al. (1985)} compiled data on 629 patients with homocystinuria collected from all parts of the world. Among patients not discovered by newborn screening, mental capabilities were higher in B6-responsive patients (mean IQ, 79) than in B6-nonresponsive patients (mean IQ, 57). Time-to-event curves for other major clinical abnormalities were also presented. For untreated B6-responsive and B6-nonresponsive patients, these were, respectively: chance of dislocation of lenses by age 10, 55% and 82%; chance of having clinically detected thromboembolic event by age 15, 12% and 27%; chance of radiologic detection of spinal osteoporosis by age 15, 36% and 64%,, and chance of not surviving to age 30, 4% and 23%. When initiated neonatally, methionine restriction prevented mental retardation, reduced the rate of lens dislocation, and may have reduced the incidence of seizures. Pyridoxine treatment of late-detected B6-responsive patients reduced the rate of occurrence of initial thromboembolic events. Following 586 surgical procedures, 25 postoperative thromboembolic complications occurred, of which 6 were fatal. Few abnormalities were found in the offspring of either male or female patients, and the evidence was inconclusive concerning the rate of fetal loss from mothers with untreated homocystinuria. Among patients detected neonatally, only 13% were B6-responsive as compared with 47% among late-detected B6-responders. {1:Abbott et al. (1987)} evaluated 63 patients with homocystinuria for psychiatric disturbance, intelligence, evidence of other CNS problems, and responsiveness to vitamin B6. Clinically significant psychiatric disorders were found in 51%. The average IQ was 80; IQ was lower among vitamin B6-nonresponsive patients. Hypopigmentation is a feature of homocystinuria and can be shown to be reversible in patients with pyridoxine-responsive homocystinuria. Instances have been observed in which darkening of newly growing hair is observed after initiation of pyridoxine therapy, creating a clear demarcation between the old, blond and the new, dark hair ({75:Reish et al., 1995}). The consistency of the hair also changed from a coarse to a softer texture. {103:Yap et al. (2001)} studied mental capabilities of 23 pyridoxine-nonresponsive individuals with CBS deficiency with over 339 patient-years of treatment and compared these individuals to those of 10 unaffected sibs (controls). Of the 23 individuals, 19 were diagnosed through newborn screening with early treatment, 2 were late-detected, and 2 were untreated at the time of assessment. Thirteen of the newborn-screened group who were compliant with treatment had no complications, while the remaining 6, who were poorly compliant, developed complications. Good compliance was defined by a lifetime plasma free homocysteine median of less than 11 micromole per liter. The newborn-screened good-compliance group with a mean age of 14.4 years (range 4.4-24.9) had a full-scale IQ of 105.8 (range 84-120), while the poorly compliant group with a mean age of 19.9 years (range 13.8 to 25.5) had a mean full-scale IQ of 80.8 (range 40-103). The control group had a mean age of 19.4 years and a mean IQ of 102. The 2 late-detected patients had IQs of 80 and 102 at the age of almost 19 years, while the 2 untreated patients had IQs in the mid-fifties at the age of 22 and 11 years. In a review, {88:Testai and Gorelick (2010}) noted that thromboembolic events are the most common cause of death in patients with classic homocystinuria and can manifest as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. The risk of having a vascular event is 25% before age 16 years and 50% by age 30 years. Clinical Variability: Thrombotic Hyperhomocysteinemia, CBS-Related {24:Gaustadnes et al. (2000)} found that 3 of 5 unrelated patients with severe hyperhomocysteinemia and thrombosis, but no other features of classic homocystinuria, were compound heterozygous for mutations in the CBS gene, consistent with CBS deficiency. {54:Maclean et al. (2002)} reported 2 unrelated Danish patients who presented with transient ischemic attacks at age 36 and 22 years, respectively. Biochemical studies showed increased serum homocysteine, but neither had other features of classic homocystinuria such as mental retardation, ectopia lentis, or skeletal changes. Each patient was compound heterozygous for 2 mutations in the CBS gene: one with D444N ({613381.0010}) and P422L ({613381.0013}), and the other with I278T ({613381.0004}) and S466L ({613381.0014}). In vitro functional expression studies showed that the P422L and S466L mutant proteins were catalytically active and even had higher activity than wildtype, but were impaired in regulation by AdoMet. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism. {39:Kelly et al. (2003)} reported 3 unrelated patients with premature stroke and severe hyperhomocysteinemia. Excluding tall stature in 2 patients, none had clinical features of classic homocystinuria. All had increased serum methionine and increased urinary homocystine. Molecular analysis found that each patient was heterozygous for a different CBS mutation (I278T, {613381.0004}; D444N, {613381.0010}, and G307S, {613381.0001}); however, the possibility for another unidentified CBS mutation could not be ruled out. The report expanded the phenotypic variability associated with CBS mutations to include premature stroke and hyperhomocysteinemia without the classic findings of CBS deficiency. The findings also suggested that increased serum homocysteine can be associated with early-onset stroke (see {603174}). textSectionName clinicalFeatures textSectionTitle Other Features textSectionContent {30:Harker et al. (1974)} showed endothelial desquamation in baboons chronically perfused with homocystine. In human cases of homocystinuria, they demonstrated reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen. These abnormalities were corrected by clearing the plasma of homocystine with pyridoxine (in B6-responsive cases) or by administration of dipyridamole (in B6-unresponsive cases), but not by heparin anticoagulation. Platelet function was normal in patients and in the animal model. {15:Collins and Brenton (1990)} described 2 children in whom pancreatitis was a complication of homocystinuria. One patient presented at age 6 with acute pancreatitis complicated by a pseudocyst requiring drainage on 2 occasions. The second patient presented at 15.5 years of age with severe colicky abdominal pain and a history of recurring abdominal pain for 6 years. Surgery was required for drainage of a large pseudocyst of the lesser sac in which necrotic portions of the body and tail of the pancreas were free floating. {14:Cochran et al. (1990)} described an unusual presentation of pyridoxine-unresponsive homocystinuria: an intelligent teenaged boy had had asthma from infancy and at age 14 was hospitalized for recurrent left pneumothoraces requiring chest tubes. Soon thereafter he developed a right pneumothorax and subsequently a superior sagittal sinus thrombosis with papilledema and transient right hemiparesis as well as deep venous thromboses. He was found to have a very low level of cystathionine beta-synthase despite normal eye examination, including repeated slit-lamp examinations. The homocystinuria did not respond to pyridoxine or folate administration, but was reduced by methionine restriction and betaine supplementation. {4:Bass et al. (1997)} noted that spontaneous pneumothorax had been reported previously in 2 homocystinuric patients, both with the pyridoxine-refractory form. They described an adolescent boy with the pyridoxine-responsive form who experienced 2 episodes of spontaneous pneumothorax. {51:Levy et al. (2002)} reported the results of 15 pregnancies in 11 women with homocystinuria, 5 of whom were pyridoxine-nonresponsive and 6 of whom were pyridoxine-responsive. Complications of pregnancy included preeclampsia at term in 2 pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and 2 pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced liveborn infants with normal or above-normal birth measurements. One offspring had multiple congenital anomalies that included colobomas of the iris and choroids, neural tube defect, and undescended testes. He was also mentally retarded and autistic. A second offspring had Beckwith-Wiedemann syndrome ({130650}). The remaining 10 offspring were normal at birth and remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities, and maternal thromboembolic events in this series suggested that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, {51:Levy et al. (2002)} suggested a cautious approach, which would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation. Heterozygous Carriers Based on the findings of {97:Wilcken and Wilcken (1976)}, who found an association between increased plasma homocysteine and ischemic heart disease in males under age 50 years, it was hypothesized that heterozygous CBS mutation carriers may be at increased risk for cardiovascular disease (see, e.g., {6:Boers et al., 1985}). However, there has been conflicting evidence about whether or not heterozygous mutation carriers are at increased risk (review by {29:Guttormsen et al., 2001}). In a study of 203 families, {64:Mudd et al. (1981)} could find no evidence of increased frequency of heart attacks or strokes in parents or grandparents of homocystinuric children. The data available were sufficient to exclude a 5-fold increase in cardiovascular risk for homocystinuria heterozygotes and to make very improbable a relative risk of as much as 3-fold. {64:Mudd et al. (1981)} concluded that less than 5% of homocystinuria heterozygotes are likely to have a heart attack by age 50 years. {5:Boers et al. (1985)} tested for heterozygosity for homocystinuria by the finding of pathologic homocysteinemia after methionine loading and cystathionine synthase deficiency in cultured fibroblasts. Using these biochemical screening methods, {6:Boers et al. (1985)} identified putative heterozygotes for mutations in the CBS gene ({613381}), although this was not confirmed by genetic analysis. Seven of 25 patients with occlusive peripheral vascular disease manifest before age 50, and 7 of 25 patients with occlusive cerebrovascular disease manifest before age 50, were found to have increased serum homocysteine. However, none of 25 patients with myocardial infarction manifest before age 50 had increased serum homocysteine. {44:Kozich et al. (1995)} investigated the relationship between premature occlusive arterial disease (POAD) associated with hyperhomocysteinemia and heterozygosity for mutations in the CBS gene. Molecular studies of 4 patients with POAD who had hyperhomocysteinemia and reduced CBS activities (see, e.g., {6:Boers et al., 1985}) failed to find mutations in the CBS gene in 7 of 8 alleles. The cDNAs encoded catalytically active, stable CBS that exhibited normal response to both S-adenosylmethionine and pyridoxal 5-prime-phosphate. In contrast, the screening method correctly distinguished mutant from normal alleles in all 4 obligatory CBS heterozygotes studied. {44:Kozich et al. (1995)} concluded that the homocysteinemia observed in these 4 POAD patients was not due to defective CBS protein. In an editorial, {60:Motulsky (1996)} reviewed evidence that heterozygotes for homocystinuria do not appear to have elevated homocysteine levels. They noted that the mutations responsible for 70% of homocystinuria in Ireland and 50% of homocystinuria in Holland had never been found in heterozygote state in Irish or Dutch patients, respectively, with various types of premature vascular disease. Although an I278Y mutation in the CBS gene ({613381.0004}) is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, {42:Kluijtmans et al. (1996)} found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. There is some evidence that CBS heterozygosity may interact with other risk factors to increase the risk of cardiovascular disease. {57:Mandel et al. (1996)} concluded that patients with concurrent homocystinuria due to CBS deficiency have an increased risk of thrombosis when they also have the factor V Leiden mutation ({612309.0001}). They studied 7 unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (aged 0.2 to 8 years). All 6 also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden received warfarin therapy from birth and by the age of 18 months had not had thrombosis. Of 4 patients with homocystinuria who did not have factor V Leiden, none had thrombosis (aged 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. {29:Guttormsen et al. (2001)} found that 20 heterozygotes for CBS deficiency had normal fasting homocysteine levels, but increased urinary homocysteine excretion compared to controls. An abnormal homocysteine response after methionine loading was observed in 73% of pyridoxine nonresponders and in only 33% of pyridoxine responders, but the test did not completely discriminate heterozygous mutation carriers from controls. The authors concluded that unequivocal identification of CBS carrier status required DNA analysis, and also noted that it was uncertain whether or not altered homocysteine metabolism in these individuals conveys an increased risk of cardiovascular disease. {17:Elsaid et al. (2007)} found that 34 heterozygous CBS mutation carriers had mildly increased fasting levels of homocysteine compared to controls. Heterozygous carriers also had decreased folic acid and vitamin B12 levels compared to controls, but similar vitamin B6 levels. None were reported to have had cardiovascular events. textSectionName otherFeatures textSectionTitle Diagnosis textSectionContent {85:Spaeth and Barber (1967)} described a silver-nitroprusside test that was almost completely specific for homocystine. {93:Wadman et al. (1983)} referred to the cyanide-nitroprusside reaction used in the detection of cystinuria and homocystinuria as the Brand reaction. {91:Uhlendorf and Mudd (1968)} found that cultured fibroblasts derived from normal skin, as well as cells in amniotic fluid, have cystathionine synthase activity, although the enzyme is not detectable in intact normal skin. Fibroblasts grown from the skin of homocystinuric persons are deficient in the enzyme. Neonatal Screening {72:Peterschmitt et al. (1999)} reviewed the results of neonatal screening for homocystinuria over a period of 32 years in New England. For the first 23.5 years of the review, the blood methionine cutoff value was 2 mg per deciliter (134 micromole per liter). Among the 2.2 million infants screened during that period, 8 with homocystinuria were identified, giving a frequency of 1 in 275,000. In 1990, the cutoff value was reduced to 1 mg per deciliter (67 micromole per liter). Among the 1.1 million infants screened in the subsequent 8.5 years, 7 with the disorder were identified, giving a frequency of 1 in 157,000. During the latter period, the specimens were collected from 6 of the 7 infants when they were 2 days of age or less; 5 of the 6 had blood methionine concentrations below 2 mg per deciliter. Use of the reduced cutoff level increased the false-positive rate from 0.006% to 0.03%. {72:Peterschmitt et al. (1999)} concluded that a cutoff level for blood methionine of 1 mg per deciliter in neonatal screening tests for homocystinuria should identify affected infants who have only slightly elevated concentrations of methionine and reduce the frequency of false-negative results. They commented, furthermore, that the increased false-positive rate would not represent an undue burden in terms of requests for repeat analysis. Indeed, the false-positive rates were considerably lower than those associated with neonatal screening for other disorders such as congenital adrenal hyperplasia, congenital hypothyroidism, and phenylketonuria. {29:Guttormsen et al. (2001)} concluded that abnormal response of total urinary homocysteine after methionine loading was the most sensitive test and a satisfactory way for studying mild disturbances in homocysteine metabolism. Differential Diagnosis Homocysteinemia also occurs in homocystinuria due to N(5,10)-methylenetetrahydrofolate reductase deficiency ({236250}) and in transcobalamin II deficiency ({275350}). Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro, e.g., cblE ({236270}) and cblG ({250940}). Combined methylmalonic aciduria (MMA) and homocystinuria due to defects in cobalamin include cblC ({277400}), cblD ({277410}), and cblF ({277380}). textSectionName diagnosis textSectionTitle Clinical Management textSectionContent {9:Carey et al. (1968)} suggested that folic acid in pharmacologic doses is therapeutically valuable in this disease. Decrease in urinary excretion of homocystine and increase in methionine was noted during treatment. {98:Wilcken et al. (1985)} concluded that additional benefit can be realized from betaine in B6-responsive patients. Homocysteine that is not metabolized to cystine is remethylated to methionine in reactions that use either N5-methyltetrahydrofolate or betaine (trimethylglycine) as methyl donors. {31:Harrison et al. (1998)} reviewed the management of ophthalmic complications of homocystinuria on the basis of an extraordinarily large experience with 45 patients reviewed retrospectively in Saudi Arabia. Eighty-four surgical procedures were performed on 40 patients; 82 procedures were done under general anesthesia and 2 under local anesthesia. Five patients had only medical treatment. All patients had lens subluxation or dislocation. Mental retardation was present in 29 (64%). {31:Harrison et al. (1998)} suggested that surgical treatment should be considered, especially for cases of repeated lens dislocation into the anterior chamber or pupillary block glaucoma. {26:Gerding (1998)} reviewed the ocular manifestations of homocystinuria and described a surgical approach to lens dislocation that allowed minimally invasive removal of the lens, complete preservation of the anterior vitreous cortex, and stable fixation of an artificial intraocular lens. Several reports indicated a likely role for homocysteine in the pathogenesis of atherosclerosis, including those of {99:Wilcken et al. (1983)}, {38:Kang et al. (1986)}, {89:Tsai et al. (1996)}, and {13:Chao et al. (1999)}. {77:Schnyder et al. (2001)} found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty. The benefit in relation to the vascular disease of homocystinuria would be dependent on the responsiveness of the particular mutation to this form of therapy. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma disulfide derivatives. With betaine therapy, methionine levels increase over baseline, but usually remain at levels that are not associated with adverse affects. {101:Yaghmai et al. (2002)} reported the case of a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine reached very high levels on betaine and who subsequently developed massive cerebral edema without evidence of thrombosis. They concluded that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism was uncertain. This case cautioned that methionine levels should be monitored in CBS-deficient patients on betaine and that betaine should be considered as an adjunct, not an alternative, to dietary control. {73:Pullin et al. (2002)} investigated the endothelial effect of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation and endothelium-independent responses to nitroglycerin were measured using high-resolution ultrasonic vessel wall-tracking. At baseline, plasma total homocysteine was 100.8 +/- 61.6 and 9.2 +/- 1.9 micromol/L in the patient and control groups, respectively. Flow-mediated dilatation responses were impaired in the patient group (20 +/- 40 micro m) compared with the controls (116 +/- 30 micro m). With vitamin C administration, flow-mediated dilatation responses in the patient group improved both acutely and chronically at 2 weeks and at 6 months. Flow-mediated dilatation responses in the control group were unaltered. Within both groups, neither the vascular response to nitroglycerin nor plasma homocysteine was altered. {73:Pullin et al. (2002)} concluded that vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration, and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease. textSectionName clinicalManagement textSectionTitle Biochemical Features textSectionContent From study of fibroblast lines, {19:Fowler et al. (1978)} found 3 types of cystathionine synthetase deficiency: one with no residual activity; one with reduced activity and normal affinity for the cofactor pyridoxal-phosphate; and one with reduced activity and reduced affinity for the cofactor. {83:Skovby et al. (1982)} studied fibroblast extracts from 20 patients for immunoreactive cystathionine beta-synthase antigen. Each of 14 mutant extracts with residual synthase activity had cross-reactive material (CRM) ranging from 5 to 100% of controls. There was no correlation between the percent residual activity and the percent CRM. Of 6 mutant extracts without detectable catalytic activity, 3 had no CRM, while 3 had 13%, 17%, and 26% CRM. The findings provided a basis for biochemical heterogeneity of the disorder and indicated that a wide array of mutations in the CBS gene that affect enzyme structure are responsible for the disorder. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent With a rabbit antiserum against human hepatic CBS, {84:Skovby et al. (1984)} studied the enzyme in cultured fibroblasts derived from 17 homocystinuric patients. In 15 of the 17 lines, the enzyme had subunits indistinguishable in size from the normal (molecular mass of 63 kD). Material from one homocystinuric patient showed 2 mRNA species coding for equal amounts of 2 immunoprecipitable polypeptides: one of normal size and one smaller (mass of 56 kD). The father had 2 mRNAs also; the mother had only normal mRNA. Thus, the patient is a compound heterozygote; one of his mutant alleles codes for a synthase polypeptide missing about 60 amino acids. {47:Kruger and Cox (1995)} showed that expression of 3 different CBS mutants known to be associated with reduced enzyme activity in humans failed to complement growth in the yeast assay. In addition, they used the yeast CBS assay to identify 8 mutant CBS alleles in cell lines from patients with CBS deficiency. These mutant alleles included 2 previously identified and 5 novel CBS mutations. The results also demonstrated that the yeast CBS assay can detect a large percentage of individuals heterozygous for mutations in CBS. {45:Kraus (1994)} tabulated 14 mutations in the CBS gene that he and his colleagues had demonstrated in homocystinuria. The G307S mutation ({613381.0001}) is the most common cause of homocystinuria in patients of Celtic origin. {45:Kraus (1994)} indicated that even though patients have no measurable CBS activity in their fibroblasts and despite the fact that CBS subunits are undetectable in fibroblast extracts of some of these individuals, many of them are pyridoxine-responsive. Examples were cited in which the identical genotype resulted in a different phenotype within the family. In general, G307S is a pyridoxine-nonresponsive mutation, whereas the I278T ({613381.0004}) is a pyridoxine-responsive mutation ({33:Hu et al., 1993}). {78:Sebastio et al. (1995)} identified a 68-bp insertion in exon 8 of the CBS gene ({613381.0017}) in a patient with homocystinuria and predicted that it would introduce a premature termination codon and result in a nonfunctional CBS enzyme. However, {89:Tsai et al. (1996)} found that this mutation is highly prevalent. In a case-control study involving patients with premature coronary artery disease, they identified the mutation in heterozygosity in 11.7% of controls and in slightly higher prevalence in the patients, although the difference did not reach statistical significance. In all cases, the insertion was present in cis with the 833T-C (I278T) mutation. {89:Tsai et al. (1996)} suggested that the insertion created an alternate splicing site that eliminated not only the inserted intronic sequences, but also the 833T-C mutation associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. {46:Kraus et al. (1999)} stated that 92 different disease-associated mutations of the CBS gene had been identified in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations were missense, and the vast majority of these were private mutations occurring in only 1 or a very small number of families. The 2 most frequently encountered mutations were the pyridoxine-responsive I278T ({613381.0004}) and the pyridoxine-nonresponsive G307S ({613381.0001}). Mutations due to deaminations of methylcytosines represented 53% of all point substitutions in the coding region of the CBS gene. In 6 patients from 5 Korean families with homocystinuria, {50:Lee et al. (2005)} identified 8 different mutations in the CBS gene, including 4 novel mutations. In vitro functional expression studies showed that the mutant enzymes had significantly decreased activities. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent {41:Kluijtmans et al. (1999)} investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Of 10 different mutations detected in the CBS gene, 833T-C (I278T; {613381.0004}) was predominant, being present in 23 (55%) of 42 independent alleles. At diagnosis, all 12 homozygotes for this mutation tended to have higher homocysteine levels than the 17 patients with other genotypes, but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P less than 0.01). {54:Maclean et al. (2002)} described a novel class of 3 missense mutations, including P422L ({613381.0013}) and S466L ({613381.0014}), that are located in the noncatalytic C-terminal region of CBS and yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients with premature thrombosis and homocystinuric levels of homocysteine (see {603174}), but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. These 2 mutants demonstrated a level of CBS activity comparable to that of the AdoMet-stimulated wildtype CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the 3 mutants were indistinguishable from wildtype CBS. The findings illustrated the importance of AdoMet for the regulation of homocysteine metabolism and were consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated homocysteine. {25:Gaustadnes et al. (2002)} determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene. Seven novel and 20 known mutations were detected. The G307S and I278T mutations were the most common and were present in 19% and 18% of independent alleles, respectively. Expression studies of 2 novel mutations (C109R and G347S), as well as 2 known mutations (L101P and N228K), showed complete lack of catalytic activity by the mutant proteins. {25:Gaustadnes et al. (2002)} studied the correlation between genotype and biochemical response to pyridoxine treatment in 13 pyridoxine-responsive, 21 nonresponsive, and 2 partially responsive patients. The G307S mutation always resulted in a severe nonresponsive phenotype, whereas I278T resulted in a milder B6-responsive phenotype. From their results, {25:Gaustadnes et al. (2002)} were also able to establish 3 other mild mutations: P49L, R369C, and V371M. {48:Kruger et al. (2003)} examined the relationship of the clinical and biochemical phenotypes with the genotypes of 12 CBS-deficient patients from 11 families in the state of Georgia (USA). By DNA sequencing of all of the coding exons, they identified mutations in the CBS gene in 21 of the 22 possible mutant alleles. Ten different missense mutations were identified and 1 novel splice site mutation was found. Five of the missense mutations were previously described, whereas 5 were novel. Each missense mutation was tested for function by expression in S. cerevisiae and all were found to cause decreased growth rate and to have significantly decreased levels of CBS enzyme activity. The I278T ({613381.0004}) and T353M ({613381.0015}) mutations accounted for 45% of the mutant alleles in this patient cohort. textSectionName genotypePhenotypeCorrelations textSectionTitle Pathogenesis textSectionContent Thrombotic lesions of arteries and veins are major features of homocystinuria. The observations of {74:Ratnoff (1968)} may have a bearing on the mechanism of the thrombotic accidents. Reviewing the nature of the ocular zonule, {86:Streeten (1982)} pointed out that the zonular fibers are composed of glycoprotein with a high concentration of cysteine, which undoubtedly explains their susceptibility to abnormal formation in diseases of sulfur metabolism. {16:Di Minno et al. (1993)} found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients studied. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation. {56:Malinow and Stampfer (1994)} reviewed the role of plasma homocysteine in arterial occlusive diseases. {75:Reish et al. (1995)} demonstrated that DL-homocysteine inhibits tyrosinase (TYR; see {606933}), the major pigment enzyme. The activity of tyrosinase extracted from pigmented human melanoma cells that were grown in the presence of homocysteine was reduced in comparison to that extracted from cells grown without homocysteine. Copper sulfate restored homocysteine-inhibited tyrosinase activity when added to the culture cell medium. The results suggested that the probable mechanism of the inhibition is the interaction of homocysteine with copper at the active site of tyrosinase. {59:McKusick (1966)} suggested that excess homocysteine may interfere with the normal synthesis of collagen crosslinks, thus accounting for the development of osteoporosis. {53:Lubec et al. (1996)} studied collagen synthesis and crosslinking by noninvasive tests in 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of C-terminal propeptide of type I procollagen and of plasma levels of N-terminal propeptide of procollagen type III. Collagen type I crosslinks expressed by serum C-terminal telopeptide of collagen type I in the patient group were, however, only about one-third of the values found in the control group. This significant reduction of crosslinks in the patients with homocystinuria did not correlate with serum homocysteine or homocystic acid concentrations. The data supported the disturbed crosslinking hypothesis and indicated that the bone manifestations of homocystinuria are not due to deficient collagen synthesis. In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, {96:Werstuck et al. (2001)} found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides, which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia. {34:Hubmacher et al. (2005)} noted that the skeletal and ocular findings of patients with homocystinuria resemble those seen in Marfan syndrome (MFS; {154700}), which is caused by mutation in the fibrillin-1 gene (FBN1; {134797}). By in vitro studies, {34:Hubmacher et al. (2005)} found that homocysteine concentrations in patients with homocystinuria caused structural modifications of recombinant human fibrillin-1 fragments and loss of calcium binding. These molecular changes resulted in enhanced protease sensitivity of the fibrillin fragments. The changes likely occurred through covalent modification of cysteine residues in fibrillin and/or disufide bond shuffling. The findings suggested that degradation of fibrillin-1 in the connective tissues of patients with homocystinuria plays a major role in the pathogenesis of this disorder. {35:Jakubowski et al. (2008)} found that patients with homocysteinemia due to MTHFR deficiency ({236250}) or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen ({134820}). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals. textSectionName pathogenesis textSectionTitle Population Genetics textSectionContent Homocystinuria has been observed in Japan ({87:Tada et al., 1967}) and in persons of many different ethnic extractions living in the United States ({76:Schimke et al., 1965}). {8:Carey et al. (1968)} pointed out that 27 cases had been found in Ireland. {45:Kraus (1994)} reported that the G307S mutation ({613381.0001}) in the CBS gene is the most common cause of homocystinuria in patients of Celtic origin. {22:Gallagher et al. (1995)} estimated that the G307S mutation accounted for 71% of alleles in Irish homocystinuria patients. {21:Gallagher et al. (1998)} identified 3 new CBS mutations in Irish patients. They estimated that more than 40 CBS mutations in homocystinuria in various ethnic groups had been identified. Most of these were missense mutations; however, 7 deletions had been documented, 2 of which were total deletions of exons 11 and 12. {67:Mudd et al. (1995)} found estimates of the frequency of homocystinuria ranging from 1 in 58,000 to 1 in 1,000,000 in countries that systematically screen newborns. The worldwide frequency of homocystinuria has been reported to be 1 in 344,000, while that in Ireland is much higher at 1 in 65,000, based on newborn screening and cases detected clinically. The national newborn screening program for homocystinuria in Ireland was started in 1971 using the bacterial inhibition assay. {102:Yap and Naughten (1998)} reported that a total of 1.58 million newborn infants had been screened over a 25-year period up to 1996. Twenty-five homocystinuria cases were diagnosed, 21 of whom were identified on screening. The remaining 4 cases were missed and presented clinically; 3 of these were breastfed and 1 was pyridoxine-responsive. Twenty-four of the 25 patients were nonresponsive to pyridoxine. All but one of the pyridoxine-nonresponsive cases were started on a low methionine, cystine-enhanced diet supplemented with pyridoxine, vitamin B12, and folate. The data suggested that ectopia lentis, osteoporosis, mental handicap, and thromboembolic events could be prevented by this regimen. Three patients with relatively high lifetime medians of free homocysteine developed increasing myopia, an ocular feature that often precedes ectopia lentis ({7:Burke et al., 1989}). {23:Gaustadnes et al. (1999)} stated that the I278T mutation ({613381.0004}), which results from an 833T-C insertion, is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). The frequent genetic insertion variant, 844ins68 (see {613381.0017}), which occurs in cis with the 833T-C mutation, was simultaneously sought. A surprisingly high prevalence of the 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is a benign polymorphism. This led the authors to suggest that the incidence of homocystinuria due to homozygosity for 833T-C may be at least 1 per 20,500 live births in Denmark. The 844ins68 variant was present in 10% of the Danish newborns. This neutral variant was thought to be deleted from mRNA during splicing. {36:Janosik et al. (2001)} reported that during the previous 20 years, CBS deficiency had been detected in the former Czechoslovakia with a calculated frequency of 1 in 349,000. About half of 21 Czech and Slovak patients they studied were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One-half of the mutated alleles carried either the 833T-C or the IVS11-2A-C mutation ({613381.0012}); the remaining alleles contained private mutations. The high prevalence of the 833T-C allele, which confers pyridoxine-responsiveness, was not surprising because it is one of the most prevalent pathogenic CBS mutation in whites ({46:Kraus et al., 1999}). {92:Urreizti et al. (2006)} reported a high frequency of the T191M mutation ({613381.0016}) among patients with homocystinuria from the Iberian peninsula and several South American countries. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation, which conferred a B6-nonresponsive phenotype. textSectionName populationGenetics textSectionTitle Nomenclature textSectionContent Plasma homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins ({56:Malinow and Stampfer, 1994}). {55:Malinow et al. (1989)} introduced the term hyperhomocyst(e)inemia for above-normal concentrations of plasma/serum homocysteine. {65:Mudd and Levy (1995)} noted the distinction between the term 'homocysteine,' which refers to the reduced sulfhydryl form of cysteine, and 'homocystine,' which refers to the oxidized disulfide form of cysteine (cystine). The measurement of plasma levels includes both of these homocysteine-derived moieties in either the sulfhydryl or disulfide form, but the distinction is important because many of the pathologic effects of the excess compound depend on the presence of the sulfhydryl group of homocysteine. The authors suggested use of the term hyperhomocyst(e)inemia to describe the composite of these forms, since in speech it is difficult to distinguish 'homocyst(e)ine' from 'homocysteine.' They suggested that an alternative useful in communicating orally is to substitute 'total Hcy' for homocyst(e)ine, spelling out the 'Hcy.' The term 'homocyst(e)ine' with parentheses around the 'e' in the middle of the word is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. textSectionName nomenclature textSectionTitle History textSectionContent {70:Nugent et al. (1998)} gave follow-up information on 'the first case' of homocystinuria. This was a patient who was identified during a survey of a group of mentally retarded children in Northern Ireland in 1960 by {12:Carson and Neill (1962)}. He was followed at the Royal Belfast Hospital for Sick Children until age 39 years when he was transferred to the Adult Metabolic Clinic at the Royal Victoria Hospital, Belfast. Despite early difficulties and the late start in treatment to lower his serum homocysteine, the patient had remained in reasonable health. He was initially reported at age 7 years as an unusual case of Marfan syndrome with renal abnormalities, case 4 of {52:Loughridge (1959)}. He had recovered from acute glomerulonephritis at the age of 6 years and was found to be hypertensive the next year. He was mentally slow and thin, with fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, high-arched palate, and bilateral dislocated lenses. At age 10 years, during a survey of urinary amino acid chromatography of mentally retarded people in Northern Ireland, his urine was found to contain a large quantity of homocysteine accompanied by a positive nitroprusside cyanide test ({12:Carson and Neill, 1962}). His left eye was enucleated because of staphylococcal infection after acute pupillary-block glaucoma; his right lens dislocated into the anterior chamber and had to be removed. His hypertension disappeared after removal of his left kidney at the age of 13 years; thick-walled medial hypertrophic intrarenal arteries and pads of intimal fibrous tissue were found histologically. When supplementation with pyridoxine was initiated at the age of 18 years, his plasma homocysteine fell to low normal values. Daily folic acid supplementation was added 1 year later since his plasma folate concentration was low. At age 20 years he had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years; it was considered to be angina and was successfully treated. At age 50 years, his plasma homocysteine remained low. He developed acute gout which responded to indomethacin. textSectionName history textSectionTitle Animal Model textSectionContent {95:Watanabe et al. (1995)} generated mice that were moderately and severely homocysteinemic, using homologous recombination in mouse embryonic stem cells to inactivate the Cbs gene. Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and most of them died within 5 weeks after birth. Histologic examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets (resembling the finding in some severe homocystinuric patients). Plasma homocysteine levels of the homozygotes were approximately 40 times normal. Heterozygous mutants had approximately 50% reduction in CBS mRNA and enzyme activity in the liver and had twice normal plasma homocysteine levels. {95:Watanabe et al. (1995)} concluded that homozygotes are a useful model for the clinical disorder homocystinuria and the heterozygotes should be useful for studying the role of elevated levels of homocysteine in the causation of cardiovascular disease. They noted that most of the homozygous mutant mice had eyes with delayed and narrow eye openings but without obvious histologic abnormalities. Seemingly, the homozygotes did not survive long enough to develop osteoporosis and vascular occlusions. {94:Wang et al. (2005)} engineered mice that expressed the common human mutant I278T and I278T/T424N Cbs proteins. These transgene-containing mice were then bred to Cbs +/- mice to generate Cbs -/- mice that expressed only the I278T or I278T/T424N human transgenes. Both the I278T and the I278T/T424N transgenes were able to entirely rescue the neonatal mortality phenotype of Cbs -/- mice (see {95:Watanabe et al., 1995}) despite these mice having a mean homocysteine level of 250 micromoles. The transgenic Cbs -/- animals exhibited facial alopecia, had moderate liver steatosis, and were slightly smaller than heterozygous littermates. In contrast to human CBS deficiency, these mice did not exhibit hypermethioninemia. The mutant proteins were stable in several tissues, although liver extracts had only 2 to 3% of the Cbs enzyme activity found in wildtype mice. The I278T/T424N enzyme had exactly the same activity as the I278T enzyme, indicating that T424N was unable to suppress I278T in mice. {94:Wang et al. (2005)} concluded that elevated homocysteine levels per se were not responsible for the neonatal lethality observed in Cbs -/- animals and suggested that CBS protein may have other functions in addition to its role in homocysteine catabolism. textSectionName animalModel epochCreated 518166000 editHistory carol : 11/29/2012 wwang : 10/29/2010 wwang : 10/29/2010 terry : 10/13/2010 ckniffin : 10/11/2010 terry : 9/9/2010 terry : 5/12/2010 carol : 5/5/2010 carol : 5/4/2010 ckniffin : 5/3/2010 terry : 4/30/2010 ckniffin : 4/28/2010 wwang : 9/15/2009 ckniffin : 9/3/2009 terry : 6/3/2009 terry : 4/9/2009 wwang : 4/1/2009 terry : 2/26/2009 wwang : 11/20/2008 carol : 10/8/2008 ckniffin : 5/15/2007 terry : 11/15/2006 wwang : 5/31/2006 ckniffin : 5/24/2006 wwang : 3/14/2006 ckniffin : 2/17/2006 carol : 3/17/2004 tkritzer : 2/17/2004 terry : 2/10/2004 cwells : 1/14/2004 terry : 1/12/2004 cwells : 10/8/2003 cwells : 10/6/2003 tkritzer : 8/26/2002 tkritzer : 8/23/2002 terry : 8/20/2002 ckniffin : 7/9/2002 cwells : 6/19/2002 terry : 6/14/2002 ckniffin : 5/15/2002 terry : 3/5/2002 alopez : 2/18/2002 terry : 2/8/2002 alopez : 1/18/2002 terry : 1/16/2002 carol : 1/10/2002 terry : 1/10/2002 mcapotos : 12/27/2001 cwells : 10/31/2001 carol : 10/1/2001 carol : 9/10/2001 alopez : 9/7/2001 mcapotos : 6/27/2001 mcapotos : 6/27/2001 cwells : 6/22/2001 cwells : 6/4/2001 cwells : 5/29/2001 cwells : 5/25/2001 terry : 5/15/2001 alopez : 3/8/2001 joanna : 11/9/2000 carol : 6/8/2000 carol : 4/24/2000 mcapotos : 1/19/2000 mcapotos : 1/13/2000 terry : 12/21/1999 mgross : 7/16/1999 carol : 7/15/1999 jlewis : 7/14/1999 terry : 6/30/1999 jlewis : 6/30/1999 terry : 6/18/1999 mgross : 6/16/1999 terry : 6/7/1999 mgross : 6/3/1999 mgross : 5/28/1999 terry : 5/14/1999 alopez : 4/21/1999 carol : 3/9/1999 terry : 2/25/1999 carol : 2/12/1999 terry : 2/3/1999 dkim : 12/14/1998 carol : 12/8/1998 terry : 12/2/1998 carol : 10/26/1998 carol : 10/23/1998 dkim : 10/21/1998 carol : 10/21/1998 carol : 10/21/1998 carol : 9/24/1998 terry : 9/17/1998 carol : 9/3/1998 carol : 9/2/1998 alopez : 4/29/1998 terry : 4/28/1998 carol : 4/17/1998 terry : 4/15/1998 alopez : 3/16/1998 alopez : 3/16/1998 alopez : 3/16/1998 terry : 2/25/1998 terry : 2/12/1998 mark : 2/2/1998 terry : 1/29/1998 dholmes : 1/12/1998 mark : 1/2/1998 terry : 12/19/1997 mark : 6/14/1997 terry : 6/5/1997 terry : 4/24/1997 terry : 4/21/1997 jenny : 4/4/1997 terry : 3/31/1997 mark : 2/28/1997 terry : 2/26/1997 jamie : 1/15/1997 terry : 1/10/1997 terry : 1/7/1997 terry : 12/10/1996 terry : 11/13/1996 mark : 10/21/1996 terry : 7/9/1996 terry : 7/9/1996 mark : 5/21/1996 mark : 5/21/1996 terry : 5/21/1996 mark : 4/12/1996 terry : 4/5/1996 mark : 3/6/1996 terry : 3/4/1996 mark : 1/25/1996 terry : 1/23/1996 mark : 11/6/1995 terry : 4/19/1995 carol : 2/9/1995 davew : 8/19/1994 jason : 6/17/1994 mimadm : 4/18/1994 dateUpdated Thu, 29 Nov 2012 03:00:00 EST creationDate Victor A. McKusick : 6/3/1986 epochUpdated 1354176000 referenceList reference title Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B(6)-responsiveness. mimNumber 236200 referenceNumber 1 pubmedID 3591841 source Am. J. Med. Genet. 26: 959-969, 1987. authors Abbott, M. H., Folstein, S. E., Abbey, H., Pyeritz, R. E. pubmedImages false title Abdominal aortic aneurysm in homocystinuria. mimNumber 236200 referenceNumber 2 pubmedID 747076 source Acta Chir. Scand. 144: 545-546, 1978. authors Almgren, B., Eriksson, H., Hemmingsson, A., Hillerdal, G., Larsson, E., Aberg, H. pubmedImages false source Lancet 289: 337 only, 1967. Note: Originally Volume I. mimNumber 236200 authors Barber, G. W., Spaeth, G. L. title Pyridoxine therapy in homocystinuria. (Letter) referenceNumber 3 articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=20&page=831 publisherName Springer title Spontaneous pneumothorax in association with pyridoxine-responsive homocystinuria. mimNumber 236200 referenceNumber 4 publisherAbbreviation Springer pubmedID 9427154 source J. Inherit. Metab. Dis. 20: 831-832, 1997. authors Bass, H. N., LaGrave, D., Mardach, R., Cederbaum, S. D., Fuster, C. D., Chetty, M. pubmedImages false publisherUrl http://www.springeronline.com/ title Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. mimNumber 236200 referenceNumber 5 pubmedID 3972418 source Hum. Genet. 69: 164-169, 1985. authors Boers, G. H. J., Fowler, B., Smals, A. G. H., Trijbels, F. J. M., Leermakers, A. I., Kleijer, W. J., Kloppenborg, P. W. C. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198509193131201?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. mimNumber 236200 referenceNumber 6 publisherAbbreviation ATYPON pubmedID 4033695 source New Eng. J. Med. 313: 709-715, 1985. authors Boers, G. H. J., Smals, A. G. H., Trijbels, F. J. M., Fowler, B., Bakkeren, J. A. J. M., Schoonderwaldt, H. C., Kleijer, W. J., Kloppenborg, P. W. C. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://bjo.bmj.com/cgi/pmidlookup?view=long&pmid=2751974 publisherName HighWire Press title Ocular complications in homocystinuria: early and late treated. mimNumber 236200 referenceNumber 7 publisherAbbreviation HighWire pubmedID 2751974 source Brit. J. Ophthal. 73: 427-431, 1989. authors Burke, J. P., O'Keefe, M., Bowell, R., Naughten, E. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0002-9343(68)90003-X publisherName Elsevier Science title Homocystinuria: a clinical and pathological study of nine subjects in six families. mimNumber 236200 referenceNumber 8 publisherAbbreviation ES pubmedID 5658872 source Am. J. Med. 45: 7-25, 1968. authors Carey, M. C., Donovan, D. E., Fitzgerald, O., McAuley, F. D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/0002-9343(68)90004-1 publisherName Elsevier Science title Homocystinuria. II. Subnormal serum folate levels, increased folate clearance and effects of folic acid therapy. mimNumber 236200 referenceNumber 9 publisherAbbreviation ES pubmedID 5658866 source Am. J. Med. 45: 26-31, 1968. authors Carey, M. C., Fennelly, J. J., Fitzgerald, O. pubmedImages false publisherUrl http://www.elsevier.com/ title Treatment of homocystinuria with pyridoxine: a preliminary study. mimNumber 236200 referenceNumber 10 pubmedID 5785188 source Arch. Dis. Child. 44: 387-392, 1969. authors Carson, N. A. J., Carre, I. J. pubmedImages false title Homocystinuria: a new inborn error of metabolism associated with mental deficiency. mimNumber 236200 referenceNumber 11 pubmedID 14065982 source Arch. Dis. Child. 38: 425-436, 1963. authors Carson, N. A. J., Cusworth, D. C., Dent, C. E., Field, C. M. B., Neill, D. W., Westall, R. G. pubmedImages false title Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. mimNumber 236200 referenceNumber 12 pubmedID 14018926 source Arch. Dis. Child. 37: 505-513, 1962. authors Carson, N. A. J., Neill, D. W. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0021915099002087 publisherName Elsevier Science title The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis. mimNumber 236200 referenceNumber 13 publisherAbbreviation ES pubmedID 10559524 source Atherosclerosis 147: 379-386, 1999. authors Chao, C.-L., Tsai, H.-H., Lee, C.-M., Hsu, S.-M., Kao, J.-T., Chien, K.-L., Sung, F.-C., Lee, Y.-T. pubmedImages false publisherUrl http://www.elsevier.com/ title Pyridoxine-unresponsive homocystinuria with an unusual clinical course. mimNumber 236200 referenceNumber 14 pubmedID 2333882 source Am. J. Med. Genet. 35: 519-522, 1990. authors Cochran, F. B., Sweetman, L., Schmidt, K., Barsh, G., Kraus, J., Packman, S. pubmedImages false title Pancreatitis and homocystinuria. mimNumber 236200 referenceNumber 15 pubmedID 2116556 source J. Inherit. Metab. Dis. 13: 232-233, 1990. authors Collins, J. E., Brenton, D. P. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI116715 publisherName Journal of Clinical Investigation title Abnormally high thromboxane biosynthesis in homozygous homocystinuria: evidence for platelet involvement and probucol-sensitive mechanism. mimNumber 236200 referenceNumber 16 publisherAbbreviation JCI pubmedID 8376592 source J. Clin. Invest. 92: 1400-1406, 1993. authors Di Minno, G., Davi, G., Margaglione, M., Cirillo, F., Grandone, E., Ciabattoni, G., Catalano, I., Strisciuglio, P., Andria, G., Patrono, C., Mancini, M. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(07)00205-3 publisherName Elsevier Science title Are heterocygotes (sic) for classical homocystinuria at risk of vitamin B12 and folic acid deficiency? mimNumber 236200 referenceNumber 17 publisherAbbreviation ES pubmedID 17686644 source Molec. Genet. Metab. 92: 100-103, 2007. authors Elsaid, M. F., Bener, A., Lindner, M., Alzyoud, M., Shahbek, N., Abdelrahman, M. O., Abdoh, G., Bessisso, M. S., Zschocke, J., Hoffmann, G. F. pubmedImages false publisherUrl http://www.elsevier.com/ source Proc. 10th Int. Cong. Pediat., Lisbon 274-275, 1962. mimNumber 236200 authors Field, C. M. B., Carson, N. A. J., Cusworth, D. C., Dent, C. E., Neill, D. W. title Homocystinuria, a new disorder of metabolism. (Abstract) referenceNumber 18 articleUrl http://dx.doi.org/10.1172/JCI108976 publisherName Journal of Clinical Investigation title Homocystinuria: evidence for three distinct classes of cystathionine beta-synthetase mutants in cultured fibroblasts. mimNumber 236200 referenceNumber 19 publisherAbbreviation JCI pubmedID 641146 source J. Clin. Invest. 61: 645-653, 1978. authors Fowler, B., Kraus, J., Packman, S., Rosenberg, L. E. pubmedImages false publisherUrl http://www.jci.org title Homocystinuria: vitamin B6 dependent or not? (Editorial) mimNumber 236200 referenceNumber 20 pubmedID 5791095 source Ann. Intern. Med. 71: 209-211, 1969. authors Frimpter, G. W. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(98)92771-8 publisherName Elsevier Science title Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria. mimNumber 236200 referenceNumber 21 publisherAbbreviation ES pubmedID 9889017 source Molec. Genet. Metab. 65: 298-302, 1998. authors Gallagher, P. M., Naughten, E., Hanson, N. Q., Schwichtenberg, K., Bignell, M., Yuan, M., Ward, P., Yap, S., Whitehead, A. S., Tsai, M. Y. pubmedImages false publisherUrl http://www.elsevier.com/ title High frequency (71%) of cystathionine beta-synthase mutation G307S in Irish homocystinuria patients. mimNumber 236200 referenceNumber 22 pubmedID 7581402 source Hum. Mutat. 6: 177-180, 1995. authors Gallagher, P. M., Ward, P., Tan, S., Naughten, E., Kraus, J. P., Sellar, G. C., McConnell, D. J., Graham, I., Whitehead, A. S. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199905133401915?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Prevalence of congenital homocystinuria in Denmark. (Letter) mimNumber 236200 referenceNumber 23 publisherAbbreviation ATYPON pubmedID 10328723 source New Eng. J. Med. 340: 1513 only, 1999. authors Gaustadnes, M., Ingerslev, J., Rutiger, N. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.schattauer.de/index.php?id=1268&L=1&pii=th00040554&no_cache=1 publisherName Schattauer Verlag title Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants. mimNumber 236200 referenceNumber 24 publisherAbbreviation schatt pubmedID 10780316 source Thromb. Haemost. 83: 554-558, 2000. authors Gaustadnes, M., Rudiger, N., Rasmussen, K., Ingerslev, J. pubmedImages false publisherUrl http://www.schattauer.com/ articleUrl http://dx.doi.org/10.1002/humu.10104 publisherName John Wiley & Sons, Inc. title The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. mimNumber 236200 referenceNumber 25 publisherAbbreviation Wiley pubmedID 12124992 source Hum. Mutat. 20: 117-126, 2002. authors Gaustadnes, M., Wilcken, B., Oliveriusova, J., McGill, J., Fletcher, J., Kraus, J. P., Wilcken, D. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source Europ. J. Pediat. 157 (suppl. 2): S94-S101, 1998. mimNumber 236200 authors Gerding, H. title Ocular complications and a new surgical approach to lens dislocation in homocystinuria due to cystathionine-beta-synthetase deficiency. referenceNumber 26 title The identification of homocystine in the urine. mimNumber 236200 referenceNumber 27 pubmedID 13960563 source Biochem. Biophys. Res. Commun. 9: 493-496, 1962. authors Gerritsen, T., Vaughn, J. G., Waisman, H. A. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI107170 publisherName Journal of Clinical Investigation title Homocystinuria: heterozygote detection using phytohemagglutinin-stimulated lymphocytes. mimNumber 236200 referenceNumber 28 publisherAbbreviation JCI pubmedID 4682386 source J. Clin. Invest. 52: 218, 1973. authors Goldstein, J. L., Campbell, B. K., Gartler, S. M. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1002/ajmg.1247 publisherName John Wiley & Sons, Inc. title Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype. mimNumber 236200 referenceNumber 29 publisherAbbreviation Wiley pubmedID 11343305 source Am. J. Med. Genet. 100: 204-213, 2001. authors Guttormsen, A. B., Ueland, P. M., Kruger, W. D., Kim, C. E., Ose, L., Folling, I., Refsum, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM197409122911101?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Homocystinuria: vascular injury and arterial thrombosis. mimNumber 236200 referenceNumber 30 publisherAbbreviation ATYPON pubmedID 4212055 source New Eng. J. Med. 291: 537-543, 1974. authors Harker, L. A., Slichter, S. J., Scott, C. R., Ross, R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/ publisherName Elsevier Science title Management of ophthalmic complications of homocystinuria. mimNumber 236200 referenceNumber 31 publisherAbbreviation ES pubmedID 9787359 source Ophthalmology 105: 1886-1890, 1998. authors Harrison, D. A., Mullaney, P. B., Mesfer, S. A., Awad, A. H., Dhindsa, H. pubmedImages false publisherUrl http://www.elsevier.com/ source Lancet 289: 1384 only, 1967. Note: Originally Volume I. mimNumber 236200 authors Hooft, C., Carton, D., Samyn, W. title Pyridoxine treatment in homocystinuria. (Letter) referenceNumber 32 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7506602 publisherName HighWire Press title Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. mimNumber 236200 referenceNumber 33 publisherAbbreviation HighWire pubmedID 7506602 source Hum. Molec. Genet. 2: 1857-1860, 1993. authors Hu, F. L., Gu, Z., Kozich, V., Kraus, J. P., Ramesh, V., Shih, V. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16096271 publisherName HighWire Press title Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria. mimNumber 236200 referenceNumber 34 publisherAbbreviation HighWire pubmedID 16096271 source J. Biol. Chem. 280: 34946-34955, 2005. authors Hubmacher, D., Tiedemann, K., Bartels, R., Brinckmann, J., Vollbrandt, T., Batge, B., Notbohm, H., Reinhardt, D. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=18708589 publisherName HighWire Press title Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. mimNumber 236200 referenceNumber 35 publisherAbbreviation HighWire pubmedID 18708589 source FASEB J. 22: 4071-4076, 2008. authors Jakubowski, H., Boers, G. H. J., Strauss, K. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61062-3 publisherName Elsevier Science title Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. mimNumber 236200 referenceNumber 36 publisherAbbreviation ES pubmedID 11359213 source Am. J. Hum. Genet. 68: 1506-1513, 2001. authors Janosik, M., Oliveriusova, J., Janosikova, B., Sokolova, J., Kraus, E., Kraus, J. P., Kozich, V. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=5783298 publisherName HighWire Press title Psychiatric and biochemical aspects of a case of homocystinuria. mimNumber 236200 referenceNumber 37 publisherAbbreviation HighWire pubmedID 5783298 source J. Neurol. Neurosurg. Psychiat. 32: 88-93, 1969. authors Kaeser, A. C., Rodnight, R., Ellis, B. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI112461 publisherName Journal of Clinical Investigation title Protein-bound homocyst(e)ine: a possible risk factor for coronary artery disease. mimNumber 236200 referenceNumber 38 publisherAbbreviation JCI pubmedID 3700650 source J. Clin. Invest. 77: 1482-1486, 1986. authors Kang, S.-S., Wong, P. W. K., Cook, H. Y., Norusis, M., Messer, J. V. pubmedImages false publisherUrl http://www.jci.org articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12552044 publisherName HighWire Press title Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 39 publisherAbbreviation HighWire pubmedID 12552044 source Neurology 60: 275-279, 2003. authors Kelly, P. J., Furie, K. L., Kistler, J. P., Barron, M., Picard, E. H., Mandell, R., Shih, V. E. pubmedImages false publisherUrl http://highwire.stanford.edu title On the mechanism of pyridoxine responsive homocystinuria. II. Properties of normal and mutant cystathionine beta-synthase from cultured fibroblasts. mimNumber 236200 referenceNumber 40 pubmedID 4531018 source Proc. Nat. Acad. Sci. 71: 4821-4825, 1974. authors Kim, Y. J., Rosenberg, L. E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63728-8 publisherName Elsevier Science title The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. mimNumber 236200 referenceNumber 41 publisherAbbreviation ES pubmedID 10364517 source Am. J. Hum. Genet. 65: 59-67, 1999. authors Kluijtmans, L. A. J., Boers, G. H. J., Kraus, J. P., van den Heuvel, L. P. W. J., Cruysberg, J. R. M., Trijbels, F. J. M., Blom, H. J. pubmedImages false publisherUrl http://www.elsevier.com/ title Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. mimNumber 236200 referenceNumber 42 pubmedID 8554066 source Am. J. Hum. Genet. 58: 35-41, 1996. authors Kluijtmans, L. A. J., van den Heuvel, L. P. W. J., Boers, G. H. J., Frosst, P., Stevens, E. M. B., van Oost, B. A., den Heijer, M., Trijbels, F. J. M., Rozen, R., Blom, H. J. pubmedImages false articleUrl http://archpedi.ama-assn.org/cgi/pmidlookup?view=long&pmid=6015916 publisherName HighWire Press title Dietary treatment of homocystinuria. mimNumber 236200 referenceNumber 43 publisherAbbreviation HighWire pubmedID 6015916 source Am. J. Dis. Child. 113: 98-100, 1967. authors Komrower, G. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7633411 publisherName HighWire Press title Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level. mimNumber 236200 referenceNumber 44 publisherAbbreviation HighWire pubmedID 7633411 source Hum. Molec. Genet. 4: 623-629, 1995. authors Kozich, V., Kraus, E., de Franchis, R., Fowler, B., Boers, G. H. J., Graham, I., Kraus, J. P. pubmedImages false publisherUrl http://highwire.stanford.edu title Molecular basis of phenotype expression in homocystinuria. mimNumber 236200 referenceNumber 45 pubmedID 7967489 source J. Inherit. Metab. Dis. 17: 383-390, 1994. authors Kraus, J. P. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:5<362::AID-HUMU4>3.0.CO;2-K publisherName John Wiley & Sons, Inc. title Cystathionine beta-synthase mutations in homocystinuria. mimNumber 236200 referenceNumber 46 publisherAbbreviation Wiley pubmedID 10338090 source Hum. Mutat. 13: 362-375, 1999. authors Kraus, J. P., Janosik, M., Kozich, V., Mandell, R., Shih, V., Sperandeo, M. P., Sebastio, G., de Franchis, R., Andria, G., Kluijtmans, L. A. J., Blom, H., Boers, G. H. J., Gordon, R. B., Kamoun, P., Tsai, M. Y., Kruger, W. D., Koch, H. G., Ohura, T., Gaustadnes, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8528202 publisherName HighWire Press title A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene. mimNumber 236200 referenceNumber 47 publisherAbbreviation HighWire pubmedID 8528202 source Hum. Molec. Genet. 4: 1155-1161, 1995. authors Kruger, W. D., Cox, D. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10290 publisherName John Wiley & Sons, Inc. title Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. mimNumber 236200 referenceNumber 48 publisherAbbreviation Wiley pubmedID 14635102 source Hum. Mutat. 22: 434-441, 2003. authors Kruger, W. D., Wang, L., Jhee, K. H., Singh, R. H., Elsas, L. J., II pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Maternal homocystinuria: studies of an untreated mother and fetus. mimNumber 236200 referenceNumber 49 pubmedID 7436540 source Arch. Dis. Child. 55: 721-723, 1980. authors Kurczynski, T. W., Muir, W. A., Fleisher, L. D., Palomaki, J. F., Gaull, G. E., Rassin, D. K., Abramowsky, C. pubmedImages false title Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria. mimNumber 236200 referenceNumber 50 pubmedID 16205833 source J. Hum. Genet. 50: 648-654, 2005. authors Lee, S.-J., Lee, D. H., Yoo, H.-W., Koo, S. K., Park, E.-S., Park, J.-W., Lim, H. G., Jung, S.-C. pubmedImages false articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=25&page=299 publisherName Springer title Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 51 publisherAbbreviation Springer pubmedID 12227460 source J. Inherit. Metab. Dis. 25: 299-314, 2002. authors Levy, H. L., Vargas, J. E., Waisbren, S. E., Kurczynski, T. W., Roeder, E. R., Schwartz, R. S., Rosengren, S., Prasad, C., Greenberg, C. R., Gilfix, B. M., MacGregor, D., Shih, V. E., Bao, L., Kraus, J. P. pubmedImages false publisherUrl http://www.springeronline.com/ source Quart. J. Med. 112: 531-544, 1959. mimNumber 236200 authors Loughridge, L. W. title Renal abnormalities in the Marfan syndrome. referenceNumber 52 title Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. mimNumber 236200 referenceNumber 53 pubmedID 8611653 source Biochim. Biophys. Acta 1315: 159-162, 1996. authors Lubec, B., Fang-Kircher, S., Lubec, T., Blom, H. J., Boers, G. H. J. pubmedImages false articleUrl http://dx.doi.org/10.1002/humu.10089 publisherName John Wiley & Sons, Inc. title High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. mimNumber 236200 referenceNumber 54 publisherAbbreviation Wiley pubmedID 12007221 source Hum. Mutat. 19: 641-655, 2002. authors Maclean, K. N., Gaustadnes, M., Oliveriusova, J., Janosik, M., Kraus, E., Kozich, V., Kery, V., Skovby, F., Rudiger, N., Ingerslev, J., Stabler, S. P., Allen, R. H., Kraus, J. P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=2785871 publisherName HighWire Press title Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. mimNumber 236200 referenceNumber 55 publisherAbbreviation HighWire pubmedID 2785871 source Circulation 79: 1180-1188, 1989. authors Malinow, M. R., Kang, S. S., Taylor, L. M., Wong, P. W. K., Coull, B., Inahara, T., Mukerjee, D., Sexton, G., Upson, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=8087977 publisherName HighWire Press title Role of plasma homocyst(e)ine in arterial occlusive disease. (Editorial) mimNumber 236200 referenceNumber 56 publisherAbbreviation HighWire pubmedID 8087977 source Clin. Chem. 40: 857-858, 1994. authors Malinow, M. R., Stampfer, M. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199603213341204?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis. mimNumber 236200 referenceNumber 57 publisherAbbreviation ATYPON pubmedID 8592550 source New Eng. J. Med. 334: 763-768, 1996. authors Mandel, H., Brenner, B., Berant, M., Rosenberg, N., Lanir, N., Jakobs, C., Fowler, B., Seligsohn, U. pubmedImages false publisherUrl http://www.atypon.com/ title Production of arteriosclerosis by homocystinuria. mimNumber 236200 referenceNumber 58 pubmedID 5488869 source Am. J. Path. 61: 1-12, 1970. authors McCully, K. S., Ragsdale, B. D. pubmedImages false source St. Louis: C. V. Mosby (pub.) (3rd ed.) : 1966. P. 155. mimNumber 236200 authors McKusick, V. A. title Heritable Disorders of Connective Tissue referenceNumber 59 title Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. (Editorial) mimNumber 236200 referenceNumber 60 pubmedID 8554053 source Am. J. Hum. Genet. 58: 17-20, 1996. Note: Erratum: Am. J. Hum. Genet. 58: 648 only, 1996. authors Motulsky, A. G. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198509193131210?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Vascular disease and homocysteine metabolism. (Editorial) mimNumber 236200 referenceNumber 61 publisherAbbreviation ATYPON pubmedID 4033699 source New Eng. J. Med. 313: 751-753, 1985. authors Mudd, S. H. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1172/JCI106394 publisherName Journal of Clinical Investigation title Homocystinuria due to cystathionine synthase deficiency: the effect of pyridoxine. mimNumber 236200 referenceNumber 62 publisherAbbreviation JCI pubmedID 5449710 source J. Clin. Invest. 49: 1762-1773, 1970. authors Mudd, S. H., Edwards, W. A., Loeb, P. M., Brown, M. S., Laster, L. pubmedImages false publisherUrl http://www.jci.org articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=14107447 publisherName HighWire Press title Homocystinuria: an enzymatic defect. mimNumber 236200 referenceNumber 63 publisherAbbreviation HighWire pubmedID 14107447 source Science 143: 1443-1445, 1964. authors Mudd, S. H., Finkelstein, J. D., Irreverre, F., Laster, L. pubmedImages false publisherUrl http://highwire.stanford.edu title A study of cardiovascular risk in heterozygotes for homocystinuria. mimNumber 236200 referenceNumber 64 pubmedID 7325153 source Am. J. Hum. Genet. 33: 883-893, 1981. authors Mudd, S. H., Havlik, R., Levy, H. L., McKusick, V. A., Feinleib, M. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199508033330520?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Plasma homocyst(e)ine or homocysteine? (Letter) mimNumber 236200 referenceNumber 65 publisherAbbreviation ATYPON pubmedID 7596391 source New Eng. J. Med. 333: 325 only, 1995. authors Mudd, S. H., Levy, H. L. pubmedImages false publisherUrl http://www.atypon.com/ title A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. mimNumber 236200 referenceNumber 66 pubmedID 5779140 source Biochem. Biophys. Res. Commun. 35: 121-126, 1969. authors Mudd, S. H., Levy, H. L., Abeles, R. H. pubmedImages false source New York: McGraw-Hill (7th ed.) : 1995. Pp. 1279-1327. mimNumber 236200 authors Mudd, S. H., Levy, H. L., Skovby, F. title Disorders of transsulfuration.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. 1. referenceNumber 67 title The natural history of homocystinuria due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 68 pubmedID 3872065 source Am. J. Hum. Genet. 37: 1-31, 1985. authors Mudd, S. H., Skovby, F., Levy, H. L., Pettigrew, K. D., Wilcken, B., Pyeritz, R. E., Andria, G., Boers, G. H. J., Bromberg, I. L., Cerone, R., Fowler, B., Grobe, H., Schmidt, H., Schweitzer, L. pubmedImages false title Diet-responsive proconvertin (factor VII) deficiency in homocystinuria. mimNumber 236200 referenceNumber 69 pubmedID 6842332 source J. Pediat. 102: 730-734, 1983. authors Munnich, A., Saudubray, J.-M., Dautzenberg, M.-D., Parvy, P., Ogier, H., Girot, R., Manigne, P., Frezal, J. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(05)79579-9 publisherName Elsevier Science title Long-term survival of homocystinuria: the first case. mimNumber 236200 referenceNumber 70 publisherAbbreviation ES pubmedID 9746031 source Lancet 352: 624-625, 1998. authors Nugent, A., Hadden, D. R., Carson, N. A. J. pubmedImages false publisherUrl http://www.elsevier.com/ title Treatment of homocystinuria with a low-methionine diet, supplemental cystine and a methyl donor. mimNumber 236200 referenceNumber 71 pubmedID 4175242 source Lancet 292: 474-478, 1968. Note: Originally Volume II. authors Perry, T. L., Hansen, S., Love, D. L., Crawford, L. E., Tischler, B. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199911183412103?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Reduction of false negative results in screening of newborns for homocystinuria. mimNumber 236200 referenceNumber 72 publisherAbbreviation ATYPON pubmedID 10564686 source New Eng. J. Med. 341: 1572-1576, 1999. authors Peterschmitt, M. J., Simmons, J. R., Levy, H. L. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=25&page=107 publisherName Springer title Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria. mimNumber 236200 referenceNumber 73 publisherAbbreviation Springer pubmedID 12118525 source J. Inherit. Metab. Dis. 25: 107-118, 2002. authors Pullin, C. H., Bonham, J. R., McDowell, I. F. W., Lee, P. J., Powers, H. J., Wilson, J. F., Lewis, M. J., Moat, S. J. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=5748939 publisherName HighWire Press title Activation of Hageman factor by L-homocystine. mimNumber 236200 referenceNumber 74 publisherAbbreviation HighWire pubmedID 5748939 source Science 162: 1007-1009, 1968. authors Ratnoff, O. D. pubmedImages false publisherUrl http://highwire.stanford.edu title Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 75 pubmedID 7611281 source Am. J. Hum. Genet. 57: 127-132, 1995. authors Reish, O., Townsend, D., Berry, S. A., Tsai, M. Y., King, R. A. pubmedImages false title Homocystinuria: studies of 20 families with 38 affected members. mimNumber 236200 referenceNumber 76 pubmedID 14328469 source JAMA 193: 711-719, 1965. authors Schimke, R. N., McKusick, V. A., Huang, T., Pollack, A. D. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa011364?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. mimNumber 236200 referenceNumber 77 publisherAbbreviation ATYPON pubmedID 11757505 source New Eng. J. Med. 345: 1593-1600, 2001. authors Schnyder, G., Roffi, M., Pin, R., Flammer, Y., Lange, H., Eberli, F. R., Meier, B., Turi, Z. G., Hess, O. M. pubmedImages false publisherUrl http://www.atypon.com/ title The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. mimNumber 236200 referenceNumber 78 pubmedID 7762555 source Am. J. Hum. Genet. 56: 1324-1333, 1995. authors Sebastio, G., Sperandeo, M. P., Panico, M., de Franchis, R., Kraus, J. P., Andria, G. pubmedImages false articleUrl http://archderm.ama-assn.org/cgi/pmidlookup?view=long&pmid=5048223 publisherName HighWire Press title Pyridoxine-dependent hair pigmentation in association with homocystinuria. mimNumber 236200 referenceNumber 79 publisherAbbreviation HighWire pubmedID 5048223 source Arch. Derm. 106: 228-230, 1972. authors Shelley, W. B., Rawnsley, H. M., Morrow, G., III pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM197011262832207?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Pyridoxine-unresponsive homocystinuria. mimNumber 236200 referenceNumber 80 publisherAbbreviation ATYPON pubmedID 5472941 source New Eng. J. Med. 283: 1206-1208, 1970. authors Shih, V. E., Efron, M. L. pubmedImages false publisherUrl http://www.atypon.com/ title Homocystinuria, Addisonian pernicious anaemia, and partial deletion of a G chromosome. mimNumber 236200 referenceNumber 81 pubmedID 4185434 source Lancet 294: 693-694, 1969. Note: Originally Volume II. authors Shipman, R. T., Townley, R. R. W., Danks, D. M. pubmedImages false source Acta Paediat. Scand. 321 (suppl.): 1-21, 1985. mimNumber 236200 authors Skovby, F. title Homocystinuria: clinical, biochemical and genetic aspects of cystathionine beta-synthase and its deficiency in man. referenceNumber 82 title Immunochemical studies on cultured fibroblasts from patients with homocystinuria due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 83 pubmedID 7081217 source Am. J. Hum. Genet. 34: 73-83, 1982. authors Skovby, F., Kraus, J., Redlich, C., Rosenberg, L. E. pubmedImages false title Homocystinuria: biogenesis of cystathionine beta-synthase subunits in cultured fibroblasts and in an in vitro translation system programmed with fibroblast messenger RNA. mimNumber 236200 referenceNumber 84 pubmedID 6711564 source Am. J. Hum. Genet. 36: 452-459, 1984. authors Skovby, F., Kraus, J. P., Rosenberg, L. E. pubmedImages false title Prevalence of homocystinuria among the mentally retarded: evaluation of a specific screening test. mimNumber 236200 referenceNumber 85 pubmedID 6051058 source Pediatrics 40: 586-589, 1967. authors Spaeth, G. L., Barber, G. W. pubmedImages false title The nature of the ocular zonule. mimNumber 236200 referenceNumber 86 pubmedID 6763807 source Trans. Am. Ophthal. Soc. 80: 823-854, 1982. authors Streeten, B. W. pubmedImages false title Homocystinuria: amino acid pattern of the liver. mimNumber 236200 referenceNumber 87 pubmedID 6081779 source Tohoku J. Exp. Med. 92: 325-332, 1967. authors Tada, K., Yoshida, T., Hirono, H., Arakawa, T. pubmedImages false articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=20142522 publisherName HighWire Press title Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders. mimNumber 236200 referenceNumber 88 publisherAbbreviation HighWire pubmedID 20142522 source Arch. Neurol. 67: 148-153, 2010. authors Testai, F. D., Gorelick, P. B. pubmedImages false publisherUrl http://highwire.stanford.edu title High prevalence of a mutation in the cystathionine beta-synthase gene. mimNumber 236200 referenceNumber 89 pubmedID 8940271 source Am. J. Hum. Genet. 59: 1262-1267, 1996. authors Tsai, M. Y., Bignell, M., Schwichtenberg, K., Hanson, N. Q. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM197612022952303?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Platelet survival and morphology in homocystinuria due to cystathionine synthase deficiency. mimNumber 236200 referenceNumber 90 publisherAbbreviation ATYPON pubmedID 980060 source New Eng. J. Med. 295: 1283-1286, 1976. authors Uhlemann, E. R., TenPas, J. H., Lucky, A. W., Schulman, J. D., Mudd, S. H., Shulman, N. R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=5647845 publisherName HighWire Press title Cystathionine synthase in tissue culture derived from human skin: enzyme defect in homocystinuria. mimNumber 236200 referenceNumber 91 publisherAbbreviation HighWire pubmedID 5647845 source Science 160: 1007-1009, 1968. authors Uhlendorf, B. W., Mudd, S. H. pubmedImages false publisherUrl http://highwire.stanford.edu title The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America. mimNumber 236200 referenceNumber 92 pubmedID 16479318 source J. Hum. Genet. 51: 305-313, 2006. Note: Erratum: J. Hum. Genet. 52: 388-389, 2007. authors Urreizti, R., Asteggiano, C., Bermudez, M., Cordoba, A., Szlago, M., Grosso, C., de Kremer, R. D., Vilarinho, L., D'Almeida, V., Martinez-Pardo, M., Pena-Quintana, L., Dalmau, J., Bernal, J., Briceno, I., Couce, M. L., Rodes, M., Vilaseca, M. A., Balcells, S., Grinberg, D. pubmedImages false source Europ. J. Pediat. 141: 62-63, 1983. mimNumber 236200 authors Wadman, S. K., Cats, B. P., de Bree, P. K. title Sulfite oxidase deficiency and the detection of urinary sulfite. (Letter) referenceNumber 93 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15972722 publisherName HighWire Press title Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model. mimNumber 236200 referenceNumber 94 publisherAbbreviation HighWire pubmedID 15972722 source Hum. Molec. Genet. 14: 2201-2208, 2005. authors Wang, L., Chen, X., Tang, B., Hua, X., Klein-Szanto, A., Kruger, W. D. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7878023 publisherName HighWire Press title Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. mimNumber 236200 referenceNumber 95 publisherAbbreviation HighWire pubmedID 7878023 source Proc. Nat. Acad. Sci. 92: 1585-1589, 1995. authors Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M. R., Maeda, N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI11596 publisherName Journal of Clinical Investigation title Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. mimNumber 236200 referenceNumber 96 publisherAbbreviation JCI pubmedID 11375416 source J. Clin. Invest. 107: 1263-1273, 2001. authors Werstuck, G. H., Lentz, S. R., Dayal, S., Hossain, G. S., Sood, S. K., Shi, Y. Y., Zhou, J., Maeda, N., Krisans, S. K., Malinow, M. R., Austin, R. C. pubmedImages true publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI108350 publisherName Journal of Clinical Investigation title The pathogenesis of coronary artery disease: a possible role for methionine metabolism. mimNumber 236200 referenceNumber 97 publisherAbbreviation JCI pubmedID 947949 source J. Clin. Invest. 57: 1079-1082, 1976. authors Wilcken, D. E., Wilcken, B. pubmedImages false publisherUrl http://www.jci.org title Homocystinuria due to cystathionine beta-synthase deficiency--the effects of betaine treatment in pyridoxine-responsive patients. mimNumber 236200 referenceNumber 98 pubmedID 3934499 source Metabolism 34: 1115-1121, 1985. authors Wilcken, D. E. L., Dudman, N. P. B., Tyrrell, P. A. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198308253090802?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine. mimNumber 236200 referenceNumber 99 publisherAbbreviation ATYPON pubmedID 6877313 source New Eng. J. Med. 309: 448-453, 1983. authors Wilcken, D. E. L., Wilcken, B., Dudman, N. P. B., Tyrrell, P. A. pubmedImages false publisherUrl http://www.atypon.com/ title The biosynthesis of cystathionine in patients with homocystinuria. mimNumber 236200 referenceNumber 100 pubmedID 5659087 source Pediat. Res. 2: 149-160, 1968. authors Wong, P. W. K., Schwarz, V., Komrower, G. M. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.10186 publisherName John Wiley & Sons, Inc. title Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency. mimNumber 236200 referenceNumber 101 publisherAbbreviation Wiley pubmedID 11857551 source Am. J. Med. Genet. 108: 57-63, 2002. authors Yaghmai, R., Kashani, A. H., Geraghty, M. T., Okoh, J., Pomper, M., Tangerman, A., Wagner, C., Stabler, S. P., Allen, R. H., Mudd, S. H., Braverman, N. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=21&page=738 publisherName Springer title Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. mimNumber 236200 referenceNumber 102 publisherAbbreviation Springer pubmedID 9819703 source J. Inherit. Metab. Dis. 21: 738-747, 1998. authors Yap, S., Naughten, E. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=24&page=437 publisherName Springer title The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency. mimNumber 236200 referenceNumber 103 publisherAbbreviation Springer pubmedID 11596648 source J. Inherit. Metab. Dis. 24: 437-447, 2001. authors Yap, S., Rushe, H., Howard, P. M., Naughten, E. R. pubmedImages false publisherUrl http://www.springeronline.com/ seeAlso Almgren et al. (1978); Barber and Spaeth (1967); Carson and Carre (1969); Carson et al. (1963); Field et al. (1962); Frimpter (1969); Goldstein et al. (1973); Hooft et al. (1967); Kaeser et al. (1969); Kim and Rosenberg (1974); Komrower (1967); Kurczynski et al. (1980); McCully and Ragsdale (1970); Mudd (1985); Mudd et al. (1970); Mudd et al. (1964); Mudd et al. (1969); Munnich et al. (1983); Perry et al. (1968); Shelley et al. (1972); Shih and Efron (1970); Shipman et al. (1969); Skovby (1985); Uhlemann et al. (1976); Wong et al. (1968)

entryList

entry status live allelicVariantExists true epochCreated 862383600 geneMap geneSymbols PMM2, CDG1A sequenceID 10928 phenotypeMapList phenotypeMap phenotypeMimNumber 212065 mimNumber 601785 phenotypeInheritance Autosomal recessive phenotypicSeriesMimNumber 212065 phenotypeMappingKey 3 phenotype Congenital disorder of glycosylation, type Ia chromosomeLocationStart 8891669 chromosomeSort 145 chromosomeSymbol 16 mimNumber 601785 geneInheritance None confidence C mappingMethod REa, REc, Fd, R geneName Phosphomannomutase 2 mouseMgiID MGI:1859214 mouseGeneSymbol Pmm2 computedCytoLocation 16p13.2 cytoLocation 16p13.3-p13.2 transcript uc002czf.4 chromosomeLocationEnd 8943193 chromosome 16 contributors Cassandra L. Kniffin - updated : 2/15/2012 Ada Hamosh - updated : 1/6/2012 Cassandra L. Kniffin - updated : 8/18/2009 Cassandra L. Kniffin - updated : 6/22/2007 Ada Hamosh - updated : 6/14/2007 Natalie E. Krasikov - updated : 3/12/2004 Ada Hamosh - updated : 10/2/2003 Ada Hamosh - updated : 10/2/2003 George E. Tiller - updated : 10/9/2002 Michael J. Wright - updated : 8/7/2001 Victor A. McKusick - updated : 3/8/2001 Victor A. McKusick - updated : 11/29/2000 Victor A. McKusick - updated : 11/2/2000 Victor A. McKusick - updated : 2/9/2000 Victor A. McKusick - updated : 1/7/2000 Wilson H. Y. Lo - updated : 8/19/1999 Victor A. McKusick - updated : 3/17/1999 Victor A. McKusick - updated : 10/2/1998 Victor A. McKusick - updated : 5/7/1998 Victor A. McKusick - updated : 5/30/1997 clinicalSynopsisExists false mimNumber 601785 allelicVariantList allelicVariant status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs28936415 text In a family in Sicily in which linkage studies indicated mapping of CDG Ia ({212065}) to 16p13, {11:Matthijs et al. (1997)} found that affected individuals were compound heterozygous for a 425G-A transition (R141H) and a 647A-T transversion (N216I; {601785.0002}) in the PMM2 gene. Among 18 unrelated Danish patients with CDG Ia, {6:Kjaergaard et al. (1998)} found that this and the F119L mutation ({601785.0006}) accounted for 88% of all mutations. Each was found in 16 of 36 PMM2 alleles. {10:Matthijs et al. (1999)} commented on the intriguing observation of the total lack of patients homozygous for the common R141H mutation. The residual activity of the in vitro expressed R141H recombinant protein is almost zero, supporting the inference that homozygosity for this mutation is lethal early in development. Patients homozygous for the relatively frequent F119L mutation have been found, and 1 patient homozygous for the D65Y mutation ({601785.0005}) has been identified. In these patients, the residual activity of the deficient enzyme was, in the words of {10:Matthijs et al. (1999)}, 'relatively pronounced.' {19:Schollen et al. (2000)} determined the frequency of the R141H mutation in 2 normal populations: in neonates of Dutch origin, 1 in 79 were carriers, whereas in the Danish population, a carrier frequency of 1 in 60 was found. These figures were clearly in disequilibrium with the frequency of CDG Ia that had been estimated at 1 in 80,000 and 1 in 40,000 in these populations. Haplotype analysis of 43 patients with the R141H mutation of different geographic origins indicated that it is an old mutation in the Caucasian population. Based on the new data, the disease frequency was calculated at 1 in 20,000 in these populations. The authors concluded that the disease was probably underdiagnosed. {23:Vuillaumier-Barrot et al. (2000)} identified the R141H mutation in 9 of 22 (41%) chromosomes in French patients with CDG Ia. In a male infant diagnosed with CDG Ia, {3:Bohles et al. (2001)} showed a pro113-to-leu (P113L) mutation in compound heterozygosity with the arg141-to-his mutation. {16:Quelhas et al. (2006)} found that the R141H substitution was the most common mutation among 15 Portuguese patients with CDG1A, accounting for 7 of 26 mutations (26%). The second most common mutation was D65Y ({601785.0005}), which accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a founder effect for the R141H substitution. mutations PMM2, ARG141HIS number 1 clinvarAccessions RCV000008145;;2;;;RCV000078590;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs78290141 text See {601785.0001} and {11:Matthijs et al. (1997)}. {15:Neumann et al. (2003)} identified homozygosity for the N216I mutation in a 16-month-old boy with CDG Ia. In contrast to previously reported patients, he had postnatal macrosomia and did not have inverted nipples or abnormal fat pads. His parents, who were consanguineous, were heterozygous for the mutation. The authors suggested that homozygosity for this mutation could have a specific phenotype correlation. mutations PMM2, ASN216ILE number 2 clinvarAccessions RCV000008146;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894525 text In a family from Sicily in which CDG Ia ({212065}) showed linkage to 16p13, {11:Matthijs et al. (1997)} found that members with CDG Ia were compound heterozygous for a 385G-A transition (V129M) and a 484C-T transition (R162W; {601785.0004}) in the PMM2 gene. mutations PMM2, VAL129MET number 3 clinvarAccessions RCV000008147;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894526 text See {601785.0003} and {11:Matthijs et al. (1997)}. mutations PMM2, ARG162TRP number 4 clinvarAccessions RCV000008148;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894527 text In a mutation screening of 56 patients with CDG Ia (see {212065}), {13:Matthijs et al. (1998)} identified 3 alleles (one homozygous and one compound heterozygous patient) with a G-to-T transversion at nucleotide 193, resulting in an asp65-to-tyr (D65Y) mutation. The compound heterozygous patient, who died at the age of 4 months due to hepatic insufficiency, had the R141H mutation ({601785.0001}) on the other allele. {16:Quelhas et al. (2006)} found that the R141H substitution was the most common mutation among 15 Portuguese patients with CDG1A, accounting for 7 of 26 mutations (26%). The second most common mutation was D65Y, which accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a founder effect of Iberian origin for the D65Y substitution. mutations PMM2, ASP65TYR number 5 clinvarAccessions RCV000008149;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338701 text In a mutation screening of 56 patients with CDG I (see {212065}), {13:Matthijs et al. (1998)} identified 18 occurrences of a phe119-to-leu (F119L) mutation, which resulted from a C-to-A transversion at nucleotide 357. Among 18 unrelated Danish patients with CDG1, {6:Kjaergaard et al. (1998)} found that this and the R141H mutation ({601785.0001}) accounted for 88% of all mutations. Each was found in 16 of 36 CDG1 alleles. mutations PMM2, PHE119LEU number 6 clinvarAccessions RCV000078589;;1;;;RCV000008150;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338704 text In a mutation screening of 56 patients with CDG I (see {212065}), {13:Matthijs et al. (1998)} identified 5 occurrences of an asp188-to-gly (D188G) mutation, all of which were in compound heterozygous state with the R141H mutation ({601785.0001}). An A-to-G transition at nucleotide 563 resulted in the D188G substitution. mutations PMM2, ASP188GLY number 7 clinvarAccessions RCV000008151;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894530 text In Danish cases of CDG Ia ({212065}), {6:Kjaergaard et al. (1998)} identified a G-to-C transversion at nucleotide 349, resulting in a gly117-to-arg (G117R) substitution. The mutation was present in compound heterozygous state with the common F119L mutation ({601785.0006}). mutations PMM2, GLY117ARG number 8 clinvarAccessions RCV000008152;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894531 text In Danish cases of CDG Ia ({212065}), {6:Kjaergaard et al. (1998)} identified a C-to-G transversion at nucleotide 669, resulting in an asp223-to-glu (D223E) substitution. The patient was a compound heterozygote, but the second mutation was not identified. mutations PMM2, ASP223GLU number 9 clinvarAccessions RCV000008153;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia text {2:Bjursell et al. (1998)} identified a 357C-A transversion in exon 5 of the PMM2 gene as the change associated with the frequent 'haplotype A' found in CDG Ia ({212065}) patients from western Scandinavia. The mutation created a restriction site not present in the normal allele which could be recognized by the restriction enzyme Tru9I. mutations PMM2, 357C-A number 10 clinvarAccessions RCV000008154;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338708 text In a patient with CDG Ia ({212065}), {7:Kjaergaard et al. (1999)} identified a thr237-to-arg substitution (T237R) in the PMM2 gene. The patient was a compound heterozygote for the asp223-to-glu substitution ({601785.0009}). mutations PMM2, THR237ARG number 11 clinvarAccessions RCV000008155;;1;;;RCV000078598;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338709 text In a review of PMM2 mutations causing CDG Ia ({212065}), {10:Matthijs et al. (1999)} noted that 4 patients had a 722G-C change in exon 8, resulting in a cys241-to-ser (C241S) mutation in a nonconserved region in the C-terminal part of the PMM2 protein. {23:Vuillaumier-Barrot et al. (2000)} determined that this mutation decreases the activity of PMM2 by only 50%. {5:Grunewald et al. (2001)} found that the C241S mutation was present in compound heterozygous state in 6 of 9 patients with a mild form of CDG Ia. {23:Vuillaumier-Barrot et al. (2000)} identified the C241S mutation in compound heterozygosity with R141H ({601785.0001}) in a French patient with CDG Ia. mutations PMM2, CYS241SER number 12 clinvarAccessions RCV000008156;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338702 text In 3 of 22 chromosomes in French patients with CDG Ia ({212065}), {23:Vuillaumier-Barrot et al. (2000)} identified a 395T-C transition in exon 5 of the PMM2 gene, resulting in an ile132-to-thr (I132T) substitution. Two of the patients were compound heterozygous for I132T and R141H ({601785.0001}), and the other was compound heterozygous for I132T and another pathogenic PMM2 mutation. mutations PMM2, ILE132THR number 13 clinvarAccessions RCV000008157;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338707 text In 3 of 22 chromosomes in French patients with CDG Ia ({212065}), {23:Vuillaumier-Barrot et al. (2000)} identified a 691G-A transition in exon 8 in the PMM2 gene, resulting in a val231-to-met (V231M) substitution. All patients were compound heterozygous for V231M and R141H ({601785.0001}). mutations PMM2, VAL231MET number 14 clinvarAccessions RCV000008158;;2;;;RCV000078597;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894532 text In a French patient with CDG1A ({212065}), {23:Vuillaumier-Barrot et al. (2000)} identified compound heterozygosity for 2 mutations in the PMM2 gene: a 26G-A transition in exon 1 resulting in a cys9-to-tyr (C9Y) substitution and R141H ({601785.0001}). mutations PMM2, CYS9TYR number 15 clinvarAccessions RCV000008159;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894533 text In a French patient with CDG Ia ({212065}), {23:Vuillaumier-Barrot et al. (2000)} identified a 95TA-GC change in exon 2 of the PMM2 gene, resulting in a leu32-to-arg (L32R) substitution. The second mutant allele was not identified. mutations PMM2, LEU32ARG number 16 clinvarAccessions RCV000008160;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338706 text In a French patient with CDG Ia ({212065}), {23:Vuillaumier-Barrot et al. (2000)} identified compound heterozygosity for 2 mutations in the PMM2 gene: a 677C-G transversion in exon 8, resulting in a thr226-to-ser (T226S) substitution, and R141H ({601785.0001}). mutations PMM2, THR226SER number 17 clinvarAccessions RCV000008161;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs80338700 text In a male infant diagnosed with CDG Ia ({212065}), {3:Bohles et al. (2001)} identified compound heterozygosity for a pro113-to-leu (P113L) and an arg141-to-his (R141H; {601785.0001}) substitution. mutations PMM2, PRO113LEU number 18 clinvarAccessions RCV000078588;;1;;;RCV000008162;;2 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia text In a patient with CDG Ia ({212065}), {18:Schollen et al. (2007)} detected compound heterozygosity for a V231M mutation in PMM2 ({601785.0014}) and a deep intronic point mutation, notated as 639-15479C-T in the cDNA. The latter variant activated a cryptic splice site which resulted in in-frame insertion of a pseudoexon of 123 bp between exons 7 and 8. {22:Vega et al. (2009)} referred to this mutation as 640-15479C-T or IVS7-15479C-T. In vitro functional expression assays showed that the mutation activated a pseudoexon sequence in intron 7. Antisense morpholino oligonucleotides targeted to the 3- and 5-prime cryptic splice sites rescued the defect and allowed correctly spliced mRNA to be translated into a functional protein. mutations PMM2, IVS7, C-T number 19 clinvarAccessions RCV000008163;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs104894534 text In a patient with CDG Ia ({212065}), {18:Schollen et al. (2007)} detected compound heterozygosity for a val44-to-ala (V44A) mutation in PMM2 arising from a 131T-C transition in exon 2, and a large deletion ({601785.0021}). mutations PMM2, VAL44ALA number 20 clinvarAccessions RCV000008164;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia text In a patient with CDG Ia ({212065}), {18:Schollen et al. (2007)} found compound heterozygosity for a missense mutation in the PMM2 gene ({601785.0020}) and an Alu retrotransposition-mediated complex deletion of approximately 28 kb encompassing exon 8. mutations PMM2, 28-KB DEL number 21 clinvarAccessions RCV000008165;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia text In a patient with CDG Ia ({212065}), {22:Vega et al. (2009)} identified compound heterozygosity for 2 mutations in the PMM2 gene: a G-to-C transversion in intron 3 (IVS3-1G-C), resulting in the skipping of exons 3 and 4, and the L32R ({601785.0016}) mutation. Western blot analysis showed 28% residual protein. mutations PMM2, IVS3AS, G-C, -1 number 22 clinvarAccessions RCV000008166;;1 status live name CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia dbSnps rs387906824 text In family 8307998, {14:Najmabadi et al. (2011)} identified a homozygous A-to-T transversion in the PMM2 gene at genomic coordinate Chr:16:8807735 (NCBI36), resulting in a tyr106-to-phe (Y106F) substitution, in 3 sibs with mild intellectual disability, thin upper lip, flat nasal bridge, and strabismus, who were diagnosed with glycosylation disorder CDG Ia ({212065}). The parents, who were first cousins, were carriers, and they had 5 healthy children. mutations PMM2, TYR106PHE number 23 clinvarAccessions RCV000023149;;1 prefix * titles preferredTitle PHOSPHOMANNOMUTASE 2; PMM2 textSectionList textSection textSectionTitle Description textSectionContent The PMM2 gene encodes phosphomannomutase ({EC 5.4.2.8}), an enzyme necessary for the synthesis of GDP-mannose. textSectionName description textSectionTitle Cloning textSectionContent {12:Matthijs et al. (1997)} identified phosphomannomutase-1 (PMM1; {601786}) by database searching for human cDNAs with similarity to Candida or yeast phosphomannomutase. Biochemical studies of PMM1 and phosphomannomutases from rat and human liver provided evidence for the existence in mammals of a second phosphomannomutase with different kinetic and antigenic properties. By database searching for sequences similar to that of PMM1, {11:Matthijs et al. (1997)} identified identified and subsequently cloned a PMM2 cDNA. The deduced 246-amino acid PMM2 protein shares 66% and 57% sequence identity with PMM1 and yeast phosphomannomutase, respectively. textSectionName cloning textSectionTitle Mapping textSectionContent {11:Matthijs et al. (1997)} mapped the PMM2 gene to 16p13 by Southern blot analysis of a genomic mapping panel and by hybridization to DNA from YACs previously assigned to that chromosomal region (D16S406 to D16S404). {2:Bjursell et al. (1998)} achieved refined mapping of the PMM2 gene by analysis of radiation hybrids. textSectionName mapping textSectionTitle Gene Structure textSectionContent {20:Schollen et al. (1998)} determined the PMM2 intron/exon structure and identified 8 exons. textSectionName geneStructure textSectionTitle Molecular Genetics textSectionContent {21:Van Schaftingen and Jaeken (1995)} identified a deficiency of phosphomannomutase activity in patients with carbohydrate-deficient glycoprotein syndrome type Ia (CDG1A; {212065}). In 16 patients with CDG1A from different geographic origins and with a documented phosphomannomutase deficiency, {11:Matthijs et al. (1997)} identified 11 different missense mutations in PMM2 (see, e.g., {601785.0001}-{601785.0004}). {13:Matthijs et al. (1998)} described the results of an exhaustive mutation analysis of the PMM2 gene in 56 patients with documented PMM deficiency from different geographic origins. By SSCP analysis and by sequencing, they identified 23 different missense mutations and a single-basepair deletion in 99% of the disease chromosomes. The R141H mutation ({601785.0001}) was found in 43 of 112 disease alleles. However, this mutation was never observed in the homozygous state, suggesting that homozygosity is incompatible with live birth. Homozygous mutations were found in other patients (D65Y, {601785.0005} and F119L, {601785.0006}). One particular genotype, R141H/D188G ({601785.0007}), which was prevalent in Belgium and the Netherlands, was associated with a severe phenotype and a high mortality. Apart from this, there was only a limited relation between the genotype and the clinical phenotype. {6:Kjaergaard et al. (1998)} identified 34 mutations on 36 disease chromosomes in 18 unrelated Danish patients with CDG1. All patients had less than 15% residual activity of phosphomannomutase. Two mutations accounted for 88% of all mutations: F119L ({601785.0006}) and R141H ({601785.0001}) were each found in 16 of 36 CDG1 alleles. These 2 new mutations were found to be in linkage disequilibrium with 2 different alleles of the marker D16S3020, suggesting that there is 1 ancestral origin for each mutation. Two new mutations, G117R and D223E, were identified also. As reported by others, no patient was homozygous for either of the 2 common mutations. This could be interpreted as indicating that homozygosity for these mutations is lethal or, on the other hand, so benign that such patients are not detected. {8:Kondo et al. (1999)} identified 3 missense mutations in the PMM2 gene in 2 unrelated Japanese families with CDG1. The mutations occurred in exons 5 and 8, as have most of the mutations identified in the Caucasian population. {7:Kjaergaard et al. (1999)} determined the PMM2 genotypes of 22 unrelated Danish patients with CDG Ia. The largest proportion (18) had the genotype R141H/F119L. R141H was present in heterozygous state in 1 patient, while F119L was homozygous in 1 patient and heterozygous with G117R in another. The lack of patients homozygous for R141H was statistically highly significant. To investigate the effect of PMM2 mutations on phosphomannomutase activity, {7:Kjaergaard et al. (1999)} cloned the cDNA into a vector. Following the introduction of mutations into the PMM2 cDNA by site-specific mutagenesis, wildtype and mutant PMM2 cDNAs were expressed in E. coli, and the activity of PMM2 was determined by an enzymatic assay. Recombinant R141H, G117R, and T237R ({601785.0011}) PMM2 had no detectable catalytic activity. F119L PMM2 had 25% of the activity of wildtype. Each of the 22 patients had at least 1 mutation that retained residual PMM2 activity. The results supported the hypotheses that a genotype conveying residual PMM2 catalytic activity is required for survival, and that homozygosity for R141H impairs PMM2 to a degree incompatible with life. {10:Matthijs et al. (1999)} reviewed the molecular basis of CDG Ia. {9:Matthijs et al. (2000)} collated data from 6 research and diagnostic laboratories involved in searching for PMM2 mutations. In total, they listed 58 different mutations found in 249 patients from 23 countries. {1:Bjursell et al. (2000)} performed a mutation screen on 61 CDG Ia patients, 37 of whom were from Scandinavian countries. They succeeded in detecting more than 95% of the mutations, all of them missense mutations. Seven were found only in Scandinavian families. Of the 20 mutations found, 10 had not previously been reported. The R141H ({601785.0001}) and F119L ({601785.0006}) mutations accounted for 58% of the mutations detected. The most common genotype was compound heterozygosity for these 2 mutations (36%). Although 2 patients were homozygous for F119L, no patient was homozygous for the most common mutation, R141H. Most mutations were located in exon 5 or exon 8, while no mutation was detected in exon 2. When the frequency of each mutation was considered, exon 5 comprised 61% of the mutations. Thus, analysis of exon 5 in these patients enabled reliable and time-saving first screening in prenatal diagnostic cases. {5:Grunewald et al. (2001)} reported that 9 of 54 patients with CDG Ia had a rather high residual PMM activity in fibroblasts included in the normal range (means of controls +/- 2 SD), amounting to 35 to 70% of the mean control value. The clinical diagnosis of CDG Ia was difficult because 6 of the 9 patients belonged to a subgroup characterized by a phenotype that is milder than classic CDG Ia. These patients lacked some of the symptoms that are suggestive for the diagnosis, such as inverted nipples and abnormal fat deposition, and, as a mean, had higher residual PMM activity in fibroblasts compared with patients with moderate or severe manifestations. However, they all showed mild mental retardation, hypotonia, cerebellar hypoplasia, and strabismus. All of them had an abnormal serum transferrin pattern and a significantly reduced PMM activity in leukocytes. Of the 9 patients with mild presentation, 6 were compound heterozygotes for the C241S mutation ({601785.0012}), which is known to reduce PMM activity by only approximately 2-fold. {5:Grunewald et al. (2001)} suggested that intermediate PMM values in fibroblasts may mask the diagnosis of CDG Ia, which is better accomplished by measurement of PMM activity in leukocytes and mutation search in the PMM2 gene. {23:Vuillaumier-Barrot et al. (2000)} studied the activity of mutant proteins encoded by arg141 to his (R141H; {601785.0001}), cys241 to ser (C241S; {601785.0012}), cys9 to tyr (C9Y; {601785.0015}), leu32 to arg (L32R; {601785.0016}), and thr226 to ser (T226S; {601785.0017}). They found that the protein encoded by R141H had no detectable activity, while the others had increased specific activity (23 to 41% of normal levels). The authors speculated that this is the reason R141H is not seen in homozygous state since, in this form, it would most likely be lethal. Among a total of 55 patients with CDG1A, {24:Westphal et al. (2002)} found that a 911T-C (F304S) polymorphism in the ALG6 gene ({604566}) was almost twice as frequent in severely affected patients (0.41) compared to moderate or mildly affected patients (0.21). Functional expression studies showed that the F304S allele had a reduced ability to rescue defective glycosylation of an alg6-deficient strain of S. cerevisiae during rapid growth. The authors concluded that the presence of the F304S allele may act as a genetic modifier to exacerbate the clinical outcome in severely affected CDG1A patients. {4:Briones et al. (2002)} presented their experience with a diagnosis of 26 Spanish patients from 19 families with CDG Ia due to PMM deficiency. Patients in all but 1 of the families were compound heterozygous for PMM2 mutations. Eighteen different mutations were detected. In contrast to other series in which the R141H mutation represents 43 to 53% of the alleles, only 9 of 36 (25%) of the alleles had this mutation. The common European F119L mutation was not identified in any of the Spanish patients but the V44A ({601785.0020}) and D65Y ({601785.0005}) mutations probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients. Probably because of this genetic heterogeneity, Spanish patients showed very diverse phenotypes that are, in general, milder than in other series. {18:Schollen et al. (2007)} described 2 unusual truncating mutations in 2 CDG Ia patients. One was a deep intronic point mutation ({601785.0019}), and the other was an Alu retrotransposition-mediated complex deletion ({601785.0021}). {18:Schollen et al. (2007)} cautioned that detection of these mutations stresses the importance of combining PMM2 mutation screening on genomic DNA with analysis of the transcripts and/or with the enzymatic analysis of the phosphomannomutase activity, as these types of mutations would not be easily identified by PCR-based mutation analysis at the genomic level. {22:Vega et al. (2009)} found that the deep intronic mutation identified by {18:Schollen et al. (2007)} activated a pseudoexon sequence in intron 7. Antisense morpholino oligonucleotides targeted to the 3- and 5-prime cryptic splice sites rescued the defect and allowed correctly spliced mRNA to be translated into a functional protein. {14:Najmabadi et al. (2011)} performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8307998, they identified a homozygous missense mutation in the PMM2 gene ({601785.0023}) in 3 sibs with mild intellectual disability, thin upper lip, flat nasal bridge, and strabismus, who were diagnosed with glycosylation disorder CDG Ia ({212065}). The parents, who were first cousins, were carriers, and they had 5 healthy children. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {17:Schneider et al. (2012)} generated transgenic mice with homozygous or compound heterozygous hypomorphic Pmm2 alleles: R137H, which is analogous to human R141H ({601785.0001}), and F118L, which is predicted to lead to mild loss of enzyme activity. Homozygous R137H and compound heterozygous R137H/F118L mice were embryonic lethal. Homozygosity for R137H was associated with no residual enzymatic activity, whereas R137H/F118L mice had about 11% residual activity. Homozygous F118L mice were clinically similar to wildtype, with 38 to 42% residual PMM2 activity, which was sufficient to prevent pathologic consequences. Compound heterozygous R137H/F118L embryos showed very poor intrauterine growth with extensive degradation of multiple organs and evidence of hypoglycosylation of glycoproteins. Treatment of heterozygous F118L females with oral mannose in water beginning 1 week prior to mating resulted in a 2-fold increase of serum mannose concentrations and rescued the embryonic lethality of compound heterozygous R137H/F118L offspring, who survived beyond weaning. Compound heterozygous offspring under treatment showed organ development and glycosylation comparable to wildtype mice, indicating mannose-mediated normalization of glycosylation. The phenotypic rescue remained apparent even after 4-month maintenance of the offspring on normal water. The results revealed an essential role for proper glycosylation during embryogenesis and suggested that mannose administration to at-risk mothers may reduce the phenotype of offspring. textSectionName animalModel geneMapExists true editHistory carol : 02/23/2012 ckniffin : 2/15/2012 carol : 1/9/2012 terry : 1/6/2012 carol : 10/26/2010 wwang : 9/8/2009 ckniffin : 8/18/2009 carol : 6/26/2007 ckniffin : 6/26/2007 ckniffin : 6/26/2007 ckniffin : 6/26/2007 carol : 6/26/2007 ckniffin : 6/22/2007 ckniffin : 6/22/2007 ckniffin : 6/22/2007 alopez : 6/22/2007 terry : 6/14/2007 carol : 4/18/2007 carol : 3/23/2004 terry : 3/12/2004 cwells : 10/2/2003 cwells : 10/2/2003 cwells : 10/9/2002 cwells : 8/16/2001 cwells : 8/9/2001 terry : 8/7/2001 mcapotos : 3/20/2001 mcapotos : 3/14/2001 terry : 3/8/2001 mcapotos : 12/19/2000 mcapotos : 12/14/2000 terry : 11/29/2000 mcapotos : 11/16/2000 mcapotos : 11/10/2000 terry : 11/2/2000 mgross : 2/29/2000 carol : 2/17/2000 terry : 2/9/2000 carol : 1/24/2000 terry : 1/7/2000 carol : 8/19/1999 carol : 3/30/1999 terry : 3/17/1999 carol : 10/7/1998 terry : 10/2/1998 dholmes : 7/2/1998 alopez : 5/13/1998 carol : 5/8/1998 terry : 5/7/1998 dholmes : 1/16/1998 mark : 6/4/1997 mark : 6/3/1997 terry : 5/30/1997 mark : 5/16/1997 mark : 4/30/1997 mark : 4/30/1997 mark : 4/30/1997 mark : 4/30/1997 dateCreated Wed, 30 Apr 1997 03:00:00 EDT creationDate Victor A. McKusick : 4/30/1997 epochUpdated 1329984000 dateUpdated Thu, 23 Feb 2012 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1002/1098-1004(200011)16:5<395::AID-HUMU3>3.0.CO;2-T publisherName John Wiley & Sons, Inc. title PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families. mimNumber 601785 referenceNumber 1 publisherAbbreviation Wiley pubmedID 11058896 source Hum. Mutat. 16: 395-400, 2000. authors Bjursell, C., Erlandson, A., Nordling, M., Nilsson, S., Wahlstrom, J., Stibler, H., Kristiansson, B., Martinsson, T. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200234 publisherName Nature Publishing Group title Detailed mapping of the phosphomannomutase 2 (PMM2) gene and mutation detection enable improved analysis for Scandinavian CDG type I families. mimNumber 601785 referenceNumber 2 publisherAbbreviation NPG pubmedID 9887379 source Europ. J. Hum. Genet. 6: 603-611, 1998. authors Bjursell, C., Wahlstrom, J., Berg, K., Stibler, H., Kristiansson, B., Matthijs, G., Martinsson, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=24&page=858 publisherName Springer title Hyperinsulinaemic hypogycaemia: leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). mimNumber 601785 referenceNumber 3 publisherAbbreviation Springer pubmedID 11916319 source J. Inherit. Metab. Dis. 24: 858-862, 2001. authors Bohles, H., Sewell, A. C., Gebhardt, B., Reinecke-Luthge, A., Kloppel, G., Marquardt, T. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.kluweronline.com/art.pdf?issn=0141-8955&volume=25&page=635 publisherName Springer title Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia. mimNumber 601785 referenceNumber 4 publisherAbbreviation Springer pubmedID 12705494 source J. Inherit. Metab. Dis. 25: 635-646, 2002. authors Briones, P., Vilaseca, M. A., Schollen, E., Ferrer, I., Maties, M., Busquets, C., Artuch, R., Gort, L., Marco, M., van Schaftingen, E., Matthijs, G., Jaeken, J., Chabas, A. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)64087-7 publisherName Elsevier Science title High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). mimNumber 601785 referenceNumber 5 publisherAbbreviation ES pubmedID 11156536 source Am. J. Hum. Genet. 68: 347-354, 2001. authors Grunewald, S., Schollen, E., Van Schaftingen, E., Jaeken, J., Matthijs, G. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/ publisherName Nature Publishing Group title Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. mimNumber 601785 referenceNumber 6 publisherAbbreviation NPG pubmedID 9781039 source Europ. J. Hum. Genet. 6: 331-336, 1998. authors Kjaergaard, S., Skovby, F., Schwartz, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200398 publisherName Nature Publishing Group title Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli. mimNumber 601785 referenceNumber 7 publisherAbbreviation NPG pubmedID 10602363 source Europ. J. Hum. Genet. 7: 884-888, 1999. authors Kjaergaard, S., Skovby, F., Schwartz, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1999&volume=55&issue=1&spage=50 publisherName Blackwell Publishing title Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1. mimNumber 601785 referenceNumber 8 publisherAbbreviation Blackwell pubmedID 10066032 source Clin. Genet. 55: 50-54, 1999. authors Kondo, I., Mizugishi, K., Yoneda, Y., Hashimoto, T., Kuwajima, K., Yuasa, L., Shigemoto, K., Kuroda, Y. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/1098-1004(200011)16:5<386::AID-HUMU2>3.0.CO;2-Y publisherName John Wiley & Sons, Inc. title Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). mimNumber 601785 referenceNumber 9 publisherAbbreviation Wiley pubmedID 11058895 source Hum. Mutat. 16: 386-394, 2000. authors Matthijs, G., Schollen, E., Bjursell, C., Erlandson, A., Freeze, H., Imtiaz, F., Kjaergaard, S., Martinsson, T., Schwartz, M., Seta, N., Vuillaumier-Barrot, S., Westphal, V., Winchester, B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(99)92914-1 publisherName Elsevier Science title Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia). mimNumber 601785 referenceNumber 10 publisherAbbreviation ES pubmedID 10527672 source Molec. Genet. Metab. 68: 220-226, 1999. authors Matthijs, G., Schollen, E., Heykants, L., Grunewald, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng0597-88 publisherName Nature Publishing Group title Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). mimNumber 601785 referenceNumber 11 publisherAbbreviation NPG pubmedID 9140401 source Nature Genet. 16: 88-92, 1997. Note: Erratum: 16: 316 only, 1997. authors Matthijs, G., Schollen, E., Pardon, E., Veiga-Da-Cunha, M., Jaeken, J., Cassiman, J.-J., Van Schaftingen, E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(96)94536-X publisherName Elsevier Science title PMM (PMM1), the human homologue of SEC53 or yeast phosphomannomutase, is localized on chromosome 22q13. mimNumber 601785 referenceNumber 12 publisherAbbreviation ES pubmedID 9070917 source Genomics 40: 41-47, 1997. authors Matthijs, G., Schollen, E., Pirard, M., Budarf, M. L., Van Schaftingen, E., Cassiman, J.-J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63834-8 publisherName Elsevier Science title Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. mimNumber 601785 referenceNumber 13 publisherAbbreviation ES pubmedID 9497260 source Am. J. Hum. Genet. 62: 542-550, 1998. authors Matthijs, G., Schollen, E., Van Schaftingen, E., Cassiman, J.-J., Jaeken, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/nature10423 publisherName Nature Publishing Group title Deep sequencing reveals 50 novel genes for recessive cognitive disorders. mimNumber 601785 referenceNumber 14 publisherAbbreviation NPG pubmedID 21937992 source Nature 478: 57-63, 2011. authors Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., {and 33 others} pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1007/s00431-003-1278-8 publisherName Springer title Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation. mimNumber 601785 referenceNumber 15 publisherAbbreviation Springer pubmedID 12905014 source Europ. J. Pediat. 162: 710-713, 2003. authors Neumann, L. M., von Moers, A., Kunze, J., Blankenstein, O., Marquardt, T. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1111/j.1469-1809.2006.00334.x publisherName Blackwell Publishing title Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2. mimNumber 601785 referenceNumber 16 publisherAbbreviation Blackwell pubmedID 17166182 source Ann. Hum. Genet. 71: 348-353, 2006. authors Quelhas, D., Quental, R., Vilarinho, L., Amorim, A., Azevedo, L. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ source Nature Med. 18: 71-73, 2012. mimNumber 601785 authors Schneider, A., Thiel, C., Rindermann, J., DeRossi, C., Popovici, D., Hoffmann, G. F., Grone, H.-J., Korner, C. title Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice. referenceNumber 17 articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(07)00027-3 publisherName Elsevier Science title Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. mimNumber 601785 referenceNumber 18 publisherAbbreviation ES pubmedID 17307006 source Molec. Genet. Metab. 90: 408-413, 2007. authors Schollen, E., Keldermans, L., Foulquier, F., Briones, P., Chabas, A., Sanchez-Valverde, F., Adamowicz, M., Pronicka, E., Wevers, R., Matthijs, G. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200470 publisherName Nature Publishing Group title Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia). mimNumber 601785 referenceNumber 19 publisherAbbreviation NPG pubmedID 10854097 source Europ. J. Hum. Genet. 8: 367-371, 2000. authors Schollen, E., Kjaergaard, S., Legius, E., Schwartz, M., Matthijs, G. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9425221 publisherName HighWire Press title Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2-psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. mimNumber 601785 referenceNumber 20 publisherAbbreviation HighWire pubmedID 9425221 source Hum. Molec. Genet. 7: 157-164, 1998. authors Schollen, E., Pardon, E., Heykants, L., Renard, J., Doggett, N. A., Callen, D. F., Cassiman, J. J., Matthijs, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0014-5793(95)01357-1 publisherName Elsevier Science title Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. mimNumber 601785 referenceNumber 21 publisherAbbreviation ES pubmedID 8549746 source FEBS Lett. 377: 318-320, 1995. authors Van Schaftingen, E., Jaeken, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/humu.20960 publisherName John Wiley & Sons, Inc. title Functional analysis of three splicing mutations identified in the PMM2 gene: toward a new therapy for congenital disorder of glycosylation type IA. mimNumber 601785 referenceNumber 22 publisherAbbreviation Wiley pubmedID 19235233 source Hum. Mutat. 30: 795-803, 2009. authors Vega, A. I., Perez-Cerda, C., Desviat, L. R., Matthijs, G., Ugarte, M., Perez, B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=10922383 publisherName HighWire Press title Identification of four novel PMM2 mutations in congenital disorders of glycosylation (CDG) Ia French patients. mimNumber 601785 referenceNumber 23 publisherAbbreviation HighWire pubmedID 10922383 source J. Med. Genet. 37: 579-580, 2000. authors Vuillaumier-Barrot, S., Hetet, G., Barnier, A., Dupre, T., Cuer, M., de Lonlay, P., Cormier-Daire, V., Durand, G., Grandchamp, B., Seta, N. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11875054 publisherName HighWire Press title A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. mimNumber 601785 referenceNumber 24 publisherAbbreviation HighWire pubmedID 11875054 source Hum. Molec. Genet. 11: 599-604, 2002. authors Westphal, V., Kjaergaard, S., Schollen, E., Martens, K., Grunewald, S., Schwartz, M., Matthijs, G., Freeze, H. H. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease false hprdIDs 03472 nbkIDs NBK1110;;PMM2-CDG (CDG-Ia);;;NBK1332;;Congenital Disorders of N-Linked Glycosylation Pathway Overview refSeqAccessionIDs NG_009209.1 uniGenes Hs.625732 approvedGeneSymbols PMM2 nextGxDx true locusSpecificDBs http://www.euroglycanet.org/;;Congenital Disorders of Glycosylation pages flybaseIDs FBgn0036300 dermAtlas false umlsIDs C1418674 gtr true geneIDs 5373 swissProtIDs O15305 zfinIDs ZDB-GENE-030722-6 ensemblIDs ENSG00000140650,ENST00000268261 geneTests true mgiIDs MGI:1859214 ncbiReferenceSequences 192807338,530408244,530408240,530408242 genbankNucleotideSequences 74230029,164694611,221041455,148172432,5639922,148172433,221043337,221043019,19591181,2218086,511793961,511793962,164690331,221044961,29568019,62088897,14249867,146000999,158256505,148172431,12140517 proteinSequences 221043020,189069093,5639924,119605607,221043338,2218087,119605606,119605609,530408245,119605608,4557839,530408241,221044962,530408243,62088898,3024413,158256506,14249868,221041456 geneticsHomeReferenceIDs gene;;PMM2;;PMM2

entryList

entry status live allelicVariantExists true epochCreated 807519600 geneMap geneSymbols PTPN22, PEP, PTPN8, LYP sequenceID 733 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 600716 phenotypeInheritance Autosomal recessive phenotype {Diabetes, type 1, susceptibility to} phenotypeMimNumber 222100 phenotypeMappingKey 3 mimNumber 600716 phenotypeInheritance None phenotype {Rheumatoid arthritis, susceptibility to} phenotypeMimNumber 180300 phenotypeMappingKey 3 mimNumber 600716 phenotypeInheritance Autosomal dominant phenotype {Systemic lupus erythematosus susceptibility to} phenotypeMimNumber 152700 chromosomeLocationStart 114356432 chromosomeSort 733 chromosomeSymbol 1 mimNumber 600716 geneInheritance None confidence P mappingMethod A geneName Protein tyrosine phosphatase, nonreceptor-type 22 mouseMgiID MGI:107170 mouseGeneSymbol Ptpn22 computedCytoLocation 1p13.2 cytoLocation 1p13 transcript uc001eds.3 chromosomeLocationEnd 114414374 chromosome 1 contributors Ada Hamosh - updated : 10/7/2011 Paul J. Converse - updated : 2/28/2011 Ada Hamosh - updated : 2/16/2010 Ada Hamosh - updated : 9/9/2009 George E. Tiller - updated : 7/31/2009 Paul J. Converse - updated : 5/8/2009 Marla J. F. O'Neill - updated : 9/29/2008 Cassandra L. Kniffin - updated : 8/20/2008 Paul J. Converse - updated : 1/29/2008 Ada Hamosh - updated : 7/24/2007 Victor A. McKusick - updated : 5/7/2007 Victor A. McKusick - updated : 5/1/2007 Marla J. F. O'Neill - updated : 2/26/2007 Victor A. McKusick - updated : 12/1/2005 Victor A. McKusick - updated : 10/5/2005 Marla J. F. O'Neill - updated : 5/16/2005 Victor A. McKusick - updated : 3/11/2005 Victor A. McKusick - updated : 12/15/2004 Victor A. McKusick - updated : 12/7/2004 Victor A. McKusick - updated : 9/8/2004 Victor A. McKusick - updated : 7/12/2004 Paul J. Converse - updated : 2/13/2004 Jennifer P. Macke - updated : 11/20/1997 clinicalSynopsisExists false mimNumber 600716 allelicVariantList allelicVariant status live name DIABETES MELLITUS, INSULIN-DEPENDENT, SUSCEPTIBILITY TO dbSnps rs2476601 text {5:Bottini et al. (2004)} found that an 1858C-T transition in the PTPN8 gene resulting in an arg620-to-trp (R620W) amino acid substitution was associated with insulin-dependent diabetes mellitus (IDDM; {222100}). {4:Begovich et al. (2004)} found that the minor allele (T) was associated with susceptibility to rheumatoid arthritis (RA; {180300}). In a study of 525 unrelated North American white individuals with systemic lupus erythematosus (SLE; {152700}), {17:Kyogoku et al. (2004)} found an association between the R620W SNP and SLE, with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (OR = 4.37). Together with the evidence showing association of this SNP with type I diabetes and rheumatoid arthritis, the data provided compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to multiple sclerosis ({126200}), {3:Begovich et al. (2005)} genotyped 2 large, well-characterized, family-based data sets involving 748 MS-prone families. They found that the R620W polymorphism is not associated with multiple sclerosis. {10:Criswell et al. (2005)} described a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present. They found that the R620W functional SNP in PTPN22 ({dbSNP rs2476601}) conferred risk of 4 separate autoimmune phenotypes in these families: type I diabetes mellitus, RA, SLE, and Hashimoto thyroiditis ({140300}). Multiple sclerosis did not show association with the PTPN22 risk allele. These findings suggested a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggested that multiple sclerosis may have a pathogenesis that is distinct from that of RA, SLE, and type I diabetes mellitus. {21:Qu et al. (2005)} genotyped the R620W SNP in 588 nuclear families with at least 1 IDDM-affected child and 2 parents and in the 30 European CEPH family trios used in the International HapMap Project. Highly significant transmission disequilibrium was observed, with p = 1.7 x 10(-5), confirming the case-control study of {5:Bottini et al. (2004)}. However, linkage disequilibrium structure studies revealed that R620W maps to a 293-kb LD block containing numerous polymorphisms, leading {21:Qu et al. (2005)} to suggest that other potentially functional polymorphisms may be responsible for the association with type I diabetes mellitus instead of, or in addition to, R620W. {26:Vang et al. (2005)} studied T cells from carriers of the 1858C-T SNP allele of the PTPN22 gene, which predisposes to type I diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease, and other autoimmune disorders. They found that T cells with the at-risk allele produced less interleukin-2 (IL2; {147680}) upon T-cell antigen receptor (TCR) stimulation, and that the encoded phosphatase had higher catalytic activity and was a more potent negative regulator of T lymphocyte activation. {26:Vang et al. (2005)} concluded that the autoimmune-predisposing allele, 1858T, is a gain-of-function mutant. {16:Kawasaki et al. (2006)} genotyped 1,520 Japanese and 178 Korean individuals, including 732 patients with type I diabetes, 141 patients with autoimmune thyroid disease, and 825 healthy controls, for the 1858C-T SNP and found that all individuals had the wildtype homozygous C/C/ genotype. The absence of the 1858T allele in this Asian population was confirmed by 2 independent methods, PCR-RFLP and direct sequencing. {15:Kallberg et al. (2007)} compared the interaction between 2 major genetic risk factors of rheumatoid arthritis, the HLA-DRB1 shared epitope (SE) alleles (see {142857}) and the PTPN22 R620W allele ({600716.0001}), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking and the 2 genes. 'Interaction' was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--i.e., deviation from independence of penetrance of 2 unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Testing for multiplicative interaction demonstrated an interaction between the 2 genes only when the 3 studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in the Swedish and North American studies, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. {14:Huffmeier et al. (2006)} excluded a major role of the R620W allele in German psoriasis patients but suggested that other susceptibility determinants within noncoding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor (see {177900}). The {27:Wellcome Trust Case Control Consortium (2007)} described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. The authors found that {dbSNP rs6679667}, the marker within PTPN22 most associated with rheumatoid arthritis, was perfectly correlated with the previously described SNP {dbSNP 2476601}, and that the effect size was consistent with previous estimates ({13:Hinks et al., 2007}). Using flow cytometry, {22:Rieck et al. (2007)} found that T cells from individuals homozygous for 1858T, all of whom were autoimmunity patients, had a profound deficit in responsiveness to antigen stimulation. CD4 ({186940})-positive memory T cells from control subjects heterozygous for 1858T exhibited reduced responsiveness in terms of calcium mobilization, CD25 (IL2RA; {147730}) expression, and IL10 ({124092}) production compared with cells from subjects homozygous for 1858C. The presence of 1858T in control subjects was associated with increased circulating memory T cells and fewer memory B cells, which had reduced responsiveness through the B-cell receptor, compared with 1858C homozygotes. {22:Rieck et al. (2007)} concluded that the PTPN22 1858T variant is associated with a dampened response of both the T- and B-cell antigen receptors, and that the 620W isoform has enhanced inhibitory function in lymphocytes. {24:Skinningsrud et al. (2008)} presented evidence suggesting an association between the 1858T allele and autoimmune Addison disease ({240200}). In a metaanalysis of 3 studies, including their own, comprising 563 European patients with the disorder, the authors found an odds ratio of 1.36 (p = 0.003) for carriers of the T allele. {2:Barrett et al. (2009)} reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies ({27:Wellcome Trust Case Control Consortium, 2007}; {9:Cooper et al., 2008}). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including {dbSNP rs2476601} at chromosome 1p13.2 (P = 8.5 x 10(-85)). {18:Mahdi et al. (2009)} tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22, and smoking showed the strongest associations with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). {18:Mahdi et al. (2009)} concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. {1:Arechiga et al. (2009)} showed that B-cell signal transduction was impaired in individuals with the PTPN22 1858C-T SNP. This defect in signaling was characterized by a deficit in proliferation and a decrease in phosphorylation of key signaling proteins, such as SYK ({600085}), and could be reversed by PTPN22 inhibition. {1:Arechiga et al. (2009)} proposed that 1858C-T alters B-cell receptor signaling and that their findings implicate B cells in the mechanism by which the variant contributes to autoimmunity. In human T and B cells carrying the R620W mutation, {29:Zhang et al. (2011)} showed that calpain binding and cleavage were increased relative to wildtype, indicating that calpain-mediated degradation with consequently reduced expression in lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby the 620W mutation increases the risk for autoimmune disease. mutations PTPN22, ARG620TRP number 1 alternativeNames RHEUMATOID ARTHRITIS, SUSCEPTIBILITY TO, INCLUDED;; SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, INCLUDED;; HASHIMOTO THYROIDITIS, SUSCEPTIBILITY TO, INCLUDED;; ADDISON DISEASE, SUSCEPTIBILITY TO, INCLUDED clinvarAccessions RCV000009461;;1;;;RCV000009460;;1;;;RCV000009463;;1;;;RCV000009462;;1;;;RCV000009464;;1 status live name DIABETES MELLITUS, INSULIN-DEPENDENT, SUSCEPTIBILITY TO dbSnps rs2488457 text By sequencing both strands of genomic DNA from 35 healthy Japanese individuals, {16:Kawasaki et al. (2006)} identified a -1123C-G promoter SNP ({dbSNP rs2488457}) in the PTPN22 gene. In a study of 484 Japanese patients with type I diabetes (IDDM; {222100}), 317 of whom had acute-onset diabetes, and 492 healthy controls, the authors found that the heterozygous C/G genotype was associated with susceptibility to acute-onset but not slow-onset type I diabetes (OR = 1.42, p = 0.015). A similar tendency was observed in 69 Korean patients with acute-onset type I diabetes (p = 0.0105, combined OR = 1.41). mutations PTPN22, -1123, C-G number 2 clinvarAccessions RCV000009465;;1 prefix * titles alternativeTitles PEST-DOMAIN PHOSPHATASE; PEP;; LYMPHOID PHOSPHATASE; LYP;; PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE 8, FORMERLY; PTPN8, FORMERLY preferredTitle PROTEIN TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 22; PTPN22 textSectionList textSection textSectionTitle Description textSectionContent All protein tyrosine phosphatases contain a catalytic domain of approximately 200 to 300 amino acids and can be divided into membrane-bound receptors or cytoplasmic phosphatases. The intracellular location of cytoplasmic phosphatases depends on amino acid sequences outside the catalytic domain. PTPN22 is a lymphoid-specific intracellular phosphatase ({8:Cohen et al., 1999}). textSectionName description textSectionTitle Cloning textSectionContent {19:Matthews et al. (1992)} characterized 2 murine cDNAs of hematopoietic intracellular protein-tyrosine phosphatases. One was Ptpn6 ({176883}); the other was Ptpn8, which the authors called Pep. Pep was shown to contain a large C-terminal domain of approximately 500 amino acids that is rich in PEST (proline, glutamic acid, serine, and threonine) motifs. Such domains are characteristic of proteins that are rapidly degraded. The Pep cDNA was isolated by generating PCR products from mouse brain or spleen mRNA using degenerate primers designed on the basis of known phosphatase sequences. These PCR products were cloned, characterized, and used to isolate longer cDNAs from a 70Z/3 pre-B-cell-derived cDNA library. The Pep 2.7-kb cDNA was found to code for an 802-amino acid protein with a predicted molecular mass of 89.7 kD. The amino acid sequence of the phosphatase domain was about 35% similar to the phosphatase domains of other PTPases. Pep mRNA, detected by Northern blots, was most abundant in spleen and thymus, with lower amounts in lymph node and bone marrow. Pep protein, expressed both in vitro and in bacteria, was shown to have PTPase activity. By PCR screening of a human thymocyte cDNA library to identify sequences containing the conserved PTPase catalytic domain, {8:Cohen et al. (1999)} obtained cDNAs encoding 2 isoforms of PTPN8, which they termed LYP1 and LYP2. The deduced 808-amino acid LYP1 protein shares 70% overall identity with the mouse Pep protein, including 89% identity in their catalytic domains. It contains an N-terminal phosphatase catalytic domain but no hydrophobic sequences, indicating that it is most likely a nonreceptor phosphatase. LYP2 has 692 amino acids. Northern blot analysis revealed expression of a 4.4-kb LYP1 transcript in all lymphoid tissues examined, but no expression was detected in other tissues. LYP2 was expressed as a 5.2-kb transcript in lymphoid tissues, with highest levels in fetal liver, where LYP1 was not expressed. Immunoprecipitation and immunoblot analysis showed expression of 105- and 85-kD proteins for LYP1 and LYP2, respectively. Immunofluorescence microscopy demonstrated that both proteins are cytoplasmic. Immunoblot analysis detected expression of LYP1 in both B- and T-cell lines. Resting T cells expressed both isoforms, with LYP1 and LYP2 being upregulated and downregulated, respectively, after T-cell activation. textSectionName cloning textSectionTitle Gene Function textSectionContent {7:Cloutier and Veillette (1996)} used the yeast 2-hybrid system to identify proteins associated with CSK ({124095}). They found that the Src homology-3 (SH3) domain of CSK associates with a proline-rich region of PEP. {7:Cloutier and Veillette (1996)} showed that this association is highly specific and speculated that PEP may be an effector and/or regulator of CSK in T cells and other hematopoietic cells. By functional analysis, {8:Cohen et al. (1999)} confirmed that LYP has phosphatase activity. Coprecipitation analysis identified a 116-kD protein, CBL ({165360}), with which LYP appears to be constitutively associated. Overexpression of LYP reduced CBL phosphorylation. Using a phage display screen of an activated peripheral blood leukocyte cDNA library with a GRB2 ({108355}) fusion protein as bait, followed by immunoprecipitation analysis, {12:Hill et al. (2002)} found that LYP binds to the N-terminal SH3 domain of GRB2. Luciferase analysis showed that overexpression of LYP in a T-cell line inhibited transcriptional activity initiated by antibodies to the T-cell receptor (see {186830}) and the CD28 ({186760}) costimulatory molecule. By screening a library of compounds designed to bridge the PTP active site and an adjacent peripheral site, {28:Yu et al. (2007)} identified a bidentate inhibitor, I-C11, with activity against LYP, but little or no activity against other PTPs except PTP1B (PTPN1; {176885}). The crystal structure of the LYP PTP domain in the presence or absence of inhibitor revealed that the WPD loop has a half-open conformation in the apo-LYP structure and a fully open one when bound to ligand. Protein kinase C (see {176960}) phosphorylated LYP at ser35 in vitro and in vivo, and this phosphorylation impaired the ability of LYP to inactivate SRC family kinases and downregulate T-cell receptor signaling. textSectionName geneFunction textSectionTitle Mapping textSectionContent Using FISH, {8:Cohen et al. (1999)} mapped the PTPN22 gene to chromosome 1p13, a region associated with rearrangements in solid and hematopoietic tumors. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {5:Bottini et al. (2004)} presented evidence suggesting that a SNP in the PTPN22 gene, a 1858C-T transition resulting in an arg620-to-trp (R620W; {600716.0001}) substitution, is associated with insulin-dependent diabetes mellitus (IDDM; {222100}). The authors suggested a mechanism that involves a modification in T-cell activation. Rheumatoid arthritis (RA; {180300}) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. {4:Begovich et al. (2004)} reported the association of RA susceptibility with the minor allele, 1858T, of the R620W SNP in PTPN22. They showed that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with CSK ({124095}), potentially altering these proteins' normal function as negative regulators of T cell activation. The minor allele of the R620W SNP of PTPN8 implicated by {4:Begovich et al. (2004)} was the same as that associated with type I diabetes mellitus by {5:Bottini et al. (2004)}. {25:Smyth et al. (2004)} reported a further association between PTPN22 1858T and Graves thyroiditis ({275000}) and also replicated the association between PTPN22 1858T and type I diabetes mellitus in 2 large type I diabetes mellitus cohorts. {23:Siminovitch (2004)} reviewed these data, which provided compelling evidence for the involvement of PTPN22 and susceptibility to both systemic and organ-specific autoimmune diseases, consistent with longstanding predictions regarding the existence of 'general' autoimmune disease susceptibility genes. To determine whether other genetic variants in PTPN22 contribute to the development of rheumatoid arthritis, {6:Carlton et al. (2005)} sequenced the coding region of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. They then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls, and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls. Analyses of these results predicted 10 common (frequency more than 1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the W620 risk allele ({600716.0001}) was strongly associated with disease in both the sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, did not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified 2 SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least 1 additional variant in the PTPN22 gene region influence RA susceptibility. {16:Kawasaki et al. (2006)} genotyped 1,698 Asian individuals, including 732 patients with type I diabetes and 141 patients with autoimmune thyroid disease, and found that all had the wildtype homozygous 1858C/C genotype. The authors identified a novel SNP in the promoter region of the PTPN22 gene, -1123C-G ({dbSNP rs2488457}; {600716.0002}), and observed a significant association with type I diabetes in Japanese and Korean patients. The affected family-based control association test and transmission disequilibrium analysis in 472 DNA samples from multiplex Caucasian families with type I diabetes indicated that the association with type I diabetes was stronger for -1123C-G than for 1858C-T. {16:Kawasaki et al. (2006)} concluded that association of the PTPN22 gene with type I diabetes could not be attributed solely to the 1858C-T variant, and that the -1123C-G promoter SNP was a more likely causative variant. {20:Orru et al. (2009)} reported a 788G-A variant, resulting in an arg263-to-gln (R263Q; {dbSNP rs33996649}) substitution within the catalytic domain of the PTPN22 gene, that leads to reduced phosphatase activity. They genotyped 881 SLE ({152700}) patients and 1,133 healthy controls from Spain and observed a significant protective effect (p = 0.006; OR, 0.58). Three replication cohorts of Italian, Argentinian, and Caucasian North American populations failed to reach significance; however, the combined analysis of 2,093 SLE patients and 2,348 controls confirmed the protective effect (p = 0.0017; OR, 0.63). For discussion of a possible association between variation in the PTPN22 gene and psoriasis, see PSORS1 ({177900}). textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {11:Hasegawa et al. (2004)} generated viable Pep -/- mice that did not express Pep protein. Thymocyte numbers and subsets were generally similar to wildtype mice, with a marginal increase in CD5 ({153340}) expression in CD4 ({186940})/CD8 (see {186910}) double-positive thymocytes, suggesting an inhibitory role of Pep in positive but not negative selection. Older Pep-deficient mice developed splenomegaly and lymphadenopathy with an accumulation of effector/memory phenotype CD8-positive T lymphocytes. After the first 2 days of in vitro stimulation, Pep-deficient T cells demonstrated a growth advantage over wildtype T lymphocytes, with increased proliferation, cytokine secretion, and dephosphorylation of the Lck ({153390}) autoregulatory catalytic cycle. Analysis of lymphocyte function in vivo also showed enhanced antigen-dependent proliferation and increased numbers of large, well-formed germinal centers and serum IgG1, IgG2a, and IgE, but not autoantibodies or autoimmunity. {29:Zhang et al. (2011)} generated mice expressing the Lyp variant homolog Pep619W, which corresponds to the human arg620-to-trp mutation ({600716.0001}), and found that they manifest thymic and splenic enlargement accompanied by increases in T cell number, activation, and positive selection and in dendritic and B cell activation. Although Ptpn22(Pep) transcript levels were comparable in Pep619W and wildtype Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain-1 ({114220}) than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wildtype Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness may represent a mechanism whereby Lyp620W may increase risk for autoimmune disease. textSectionName animalModel geneMapExists true editHistory carol : 09/16/2013 carol : 10/27/2011 alopez : 10/17/2011 terry : 10/7/2011 mgross : 3/1/2011 terry : 2/28/2011 alopez : 3/3/2010 terry : 2/16/2010 alopez : 9/9/2009 wwang : 8/17/2009 carol : 8/4/2009 ckniffin : 8/3/2009 terry : 7/31/2009 mgross : 5/14/2009 mgross : 5/14/2009 terry : 5/8/2009 wwang : 9/29/2008 ckniffin : 9/3/2008 wwang : 8/29/2008 ckniffin : 8/20/2008 mgross : 2/7/2008 mgross : 2/7/2008 terry : 1/29/2008 terry : 8/9/2007 terry : 8/9/2007 terry : 8/9/2007 alopez : 7/24/2007 alopez : 5/7/2007 alopez : 5/7/2007 terry : 5/1/2007 wwang : 2/26/2007 ckniffin : 12/8/2006 carol : 12/6/2005 alopez : 12/5/2005 terry : 12/1/2005 alopez : 10/6/2005 terry : 10/5/2005 wwang : 5/24/2005 wwang : 5/19/2005 terry : 5/16/2005 alopez : 3/15/2005 terry : 3/11/2005 alopez : 12/16/2004 terry : 12/15/2004 alopez : 12/10/2004 alopez : 12/9/2004 terry : 12/7/2004 alopez : 9/9/2004 terry : 9/8/2004 alopez : 7/13/2004 terry : 7/12/2004 carol : 6/15/2004 mgross : 2/13/2004 dkim : 7/23/1998 alopez : 12/11/1997 alopez : 12/11/1997 mark : 4/13/1996 mark : 10/2/1995 mark : 8/4/1995 dateCreated Fri, 04 Aug 1995 03:00:00 EDT creationDate Alan F. Scott : 8/4/1995 epochUpdated 1379314800 dateUpdated Mon, 16 Sep 2013 03:00:00 EDT referenceList reference articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=19265110 publisherName HighWire Press title Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. mimNumber 600716 referenceNumber 1 publisherAbbreviation HighWire pubmedID 19265110 source J. Immun. 182: 3343-3347, 2009. authors Arechiga, A. F., Habib, T., He, Y., Zhang, X., Zhang, Z.-Y., Funk, A., Buckner, J. H. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng.381 publisherName Nature Publishing Group title Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. mimNumber 600716 referenceNumber 2 publisherAbbreviation NPG pubmedID 19430480 source Nature Genet. 41: 703-707, 2009. authors Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D. J., Stevens, H., Todd, J. A., Walker, N. M., Rich, S. S., {Type 1 Diabetes Genetics Consortium} pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62557-9 publisherName Elsevier Science title The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. (Letter) mimNumber 600716 referenceNumber 3 publisherAbbreviation ES pubmedID 15580548 source Am. J. Hum. Genet. 76: 184-187, 2005. authors Begovich, A. B., Caillier, S. J., Alexander, H. C., Penko, J. M., Hauser, S. L., Barcellos, L. F., Oksenberg, J. R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62416-1 publisherName Elsevier Science title A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. mimNumber 600716 referenceNumber 4 publisherAbbreviation ES pubmedID 15208781 source Am. J. Hum. Genet. 75: 330-337, 2004. authors Begovich, A. B., Carlton, V. E. H., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C., Ardlie, K. G., Huang, Q., Smith, A. M., Spoerke, J. M., Conn, M. T., Chang, M., {and 16 others} pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng1323 publisherName Nature Publishing Group title A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. mimNumber 600716 referenceNumber 5 publisherAbbreviation NPG pubmedID 15004560 source Nature Genet. 36: 337-338, 2004. authors Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., MacMurray, J., Meloni, G. F., Lucarelli, P., Pellecchia, M., Eisenbarth, G. S., Comings, D., Mustelin, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61005-2 publisherName Elsevier Science title PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. mimNumber 600716 referenceNumber 6 publisherAbbreviation ES pubmedID 16175503 source Am. J. Hum. Genet. 77: 567-581, 2005. authors Carlton, V. E. H., Hu, X., Chokkalingam, A. P., Schrodi, S. J., Brandon, R., Alexander, H. C., Chang, M., Catanese, J. J., Leong, D. U., Ardlie, K. G., Kastner, D. L., Seldin, M. F., Criswell, L. A., Gregersen, P. K., Beasley, E., Thomson, G., Amos, C. I., Begovich, A. B. pubmedImages false publisherUrl http://www.elsevier.com/ title Association of inhibitory tyrosine protein kinase p50(csk) with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. mimNumber 600716 referenceNumber 7 pubmedID 8890164 source EMBO J. 15: 4909-4918, 1996. authors Cloutier, J.-F., Veillette, A. pubmedImages false articleUrl http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10068674 publisherName HighWire Press title Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. mimNumber 600716 referenceNumber 8 publisherAbbreviation HighWire pubmedID 10068674 source Blood 93: 2013-2024, 1999. authors Cohen, S., Dadi, H., Shaoul, E., Sharfe, N., Roifman, C. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng.249 publisherName Nature Publishing Group title Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. mimNumber 600716 referenceNumber 9 publisherAbbreviation NPG pubmedID 18978792 source Nature Genet. 40: 1399-1401, 2008. authors Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62868-7 publisherName Elsevier Science title Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. mimNumber 600716 referenceNumber 10 publisherAbbreviation ES pubmedID 15719322 source Am. J. Hum. Genet. 76: 561-571, 2005. authors Criswell, L. A., Pfeiffer, K. A., Lum, R. F., Gonzales, B., Novitzke, J., Kern, M., Moser, K. L., Begovich, A. B., Carlton, V. E. H., Li, W., Lee, A. T., Ortmann, W., Behrens, T. W., Gregersen, P. K. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=14752163 publisherName HighWire Press title PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. mimNumber 600716 referenceNumber 11 publisherAbbreviation HighWire pubmedID 14752163 source Science 303: 685-689, 2004. authors Hasegawa, K., Martin, F., Huang, G., Tumas, D., Diehl, L., Chan, A. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0301472X01007949 publisherName Elsevier Science title The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. mimNumber 600716 referenceNumber 12 publisherAbbreviation ES pubmedID 11882361 source Exp. Hemat. 30: 237-244, 2002. authors Hill, R. J., Zozulya, S., Lu, Y.-L., Ward, K., Gishizky, M., Jallal, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=17170052 publisherName HighWire Press title Investigation of genetic variation across protein tyrosine phosphatase genes in patients with rheumatoid arthritis in the UK. mimNumber 600716 referenceNumber 13 publisherAbbreviation HighWire pubmedID 17170052 source Ann. Rheum. Dis. 66: 683-686, 2007. authors Hinks, A., Eyre, S., Barton, A., Thomson, W., Worthington, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16339849 publisherName HighWire Press title Evidence for susceptibility determinant(s) to psoriasis vulgaris in or near PTPN22 in German patients. mimNumber 600716 referenceNumber 14 publisherAbbreviation HighWire pubmedID 16339849 source J. Med. Genet. 43: 517-522, 2006. authors Huffmeier, U., Steffens, M., Burkhardt, H., Lascorz, J., Schurmeier-Horst, F., Stander, M., Kelsch, R., Baumann, C., Kuster, W., Mossner, R., Reich, K., Wienker, T. F., Traupe, H., Reis, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60942-2 publisherName Elsevier Science title Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. mimNumber 600716 referenceNumber 15 publisherAbbreviation ES pubmedID 17436241 source Am. J. Hum. Genet. 80: 867-875, 2007. authors Kallberg, H., Padyukov, L., Plenge, R. M., Ronnelid, J., Gregersen, P. K., van der Helm-van Mil, A. H. M., Toes, R. E. M., Huizinga, T. W., Klareskog, L., Alfredsson, L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.31124 publisherName John Wiley & Sons, Inc. title Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. mimNumber 600716 referenceNumber 16 publisherAbbreviation Wiley pubmedID 16470599 source Am. J. Med. Genet. 140A: 586-593, 2006. Note: Erratum: Am. J. Med. Genet. 143A: 1812-1813, 2007. authors Kawasaki, E., Awata, T., Ikegami, H., Kobayashi, T., Maruyama, T., Nakanishi, K., Shimada, A., Uga, M., Kurihara, S., Kawabata, Y., Tanaka, S., Kanazawa, Y., Lee, I., Eguchi, K., {Japanese Study Group on Type 1 Diabetes Genetics} pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63322-9 publisherName Elsevier Science title Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. mimNumber 600716 referenceNumber 17 publisherAbbreviation ES pubmedID 15273934 source Am. J. Hum. Genet. 75: 504-507, 2004. authors Kyogoku, C., Langefeld, C. D., Ortmann, W. A., Lee, A., Selby, S., Carlton, V. E. H., Chang, M., Ramos, P., Baechler, E. C., Batliwalla, F. M., Novitzke, J., Williams, A. H., {and 10 others} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng.480 publisherName Nature Publishing Group title Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. mimNumber 600716 referenceNumber 18 publisherAbbreviation NPG pubmedID 19898480 source Nature Genet. 41: 1319-1324, 2009. authors Mahdi, H., Fisher, B. A., Kallberg, H., Plant, D., Malmstrom, V., Ronnelid, J., Charles, P., Ding, B., Alfredsson, L., Padyukov, L., Symmons, D. P. M., Venables, P. J., Klareskog, L., Lundberg, K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=1373816 publisherName HighWire Press title Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. mimNumber 600716 referenceNumber 19 publisherAbbreviation HighWire pubmedID 1373816 source Molec. Cell. Biol. 12: 2396-2405, 1992. authors Matthews, R. J., Bowne, D. B., Flores, E., Thomas, M. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18981062 publisherName HighWire Press title A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. mimNumber 600716 referenceNumber 20 publisherAbbreviation HighWire pubmedID 18981062 source Hum. Molec. Genet. 18: 569-579, 2009. authors Orru, V., Tsai, S. J., Rueda, B., Fiorillo, E., Stanford, S. M., Dasgupta, J., Hartiala, J., Zhao, L., Ortego-Centeno, N., D'Alfonso, S., {Italian Collaborative Group}, Arnett, F. C., {and 11 others} pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15744042 publisherName HighWire Press title Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. (Letter) mimNumber 600716 referenceNumber 21 publisherAbbreviation HighWire pubmedID 15744042 source J. Med. Genet. 42: 266-270, 2005. authors Qu, H., Tessier, M.-C., Hudson, T. J., Polychronakos, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=17878369 publisherName HighWire Press title Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. mimNumber 600716 referenceNumber 22 publisherAbbreviation HighWire pubmedID 17878369 source J. Immun. 179: 4704-4710, 2007. authors Rieck, M., Arechiga, A., Onengut-Gumuscu, S., Greenbaum, C., Concannon, P., Buckner, J. H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1204-1248 publisherName Nature Publishing Group title PTPN22 and autoimmune disease. mimNumber 600716 referenceNumber 23 publisherAbbreviation NPG pubmedID 15565104 source Nature Genet. 36: 1248-1249, 2004. authors Siminovitch, K. A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ejhg.2008.33 publisherName Nature Publishing Group title Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. mimNumber 600716 referenceNumber 24 publisherAbbreviation NPG pubmedID 18301444 source Europ. J. Hum. Genet. 16: 977-982, 2008. authors Skinningsrud, B., Husebye, E. S., Gervin, K., Lovas, K., Blomhoff, A., Wolff, A. B., Kemp, E. H., Egeland, T., Undlien, D. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=15504986 publisherName HighWire Press title Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. mimNumber 600716 referenceNumber 25 publisherAbbreviation HighWire pubmedID 15504986 source Diabetes 53: 3020-3023, 2004. authors Smyth, D., Cooper, J. D., Collins, J. E., Heward, J. M., Franklyn, J. A., Howson, J. M. M., Vella, A., Nutland, S., Rance, H. E., Maier, L., Barratt, B. J., Guja, C., {and 11 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng1673 publisherName Nature Publishing Group title Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. mimNumber 600716 referenceNumber 26 publisherAbbreviation NPG pubmedID 16273109 source Nature Genet. 37: 1317-1319, 2005. authors Vang, T., Congia, M., Macis, M. D., Musumeci, L., Orru, V., Zavattari, P., Nika, K., Tautz, L., Tasken, K., Cucca, F., Mustelin, T., Bottini, N. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nature05911 publisherName Nature Publishing Group title Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. mimNumber 600716 referenceNumber 27 publisherAbbreviation NPG pubmedID 17554300 source Nature 447: 661-678, 2007. authors {Wellcome Trust Case Control Consortium} pubmedImages true publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18056643 publisherName HighWire Press title Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. mimNumber 600716 referenceNumber 28 publisherAbbreviation HighWire pubmedID 18056643 source Proc. Nat. Acad. Sci. 104: 19767-19772, 2007. authors Yu, X., Sun, J.-P., He, Y., Guo, X., Liu, S., Zhou, B., Hudmon, A., Zhang, Z.-Y. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng.904 publisherName Nature Publishing Group title The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. mimNumber 600716 referenceNumber 29 publisherAbbreviation NPG pubmedID 21841778 source Nature Genet. 43: 902-907, 2011. authors Zhang, J., Zahir, N., Jiang, Q., Miliotis, H., Heyraud, S., Meng, X., Dong, B., Xie, G., Qiu, F., Hao, Z., McCulloch, C. A., Keystone, E. C., Peterson, A. C., Siminovitch, K. A. pubmedImages false publisherUrl http://www.nature.com externalLinks mgiIDs MGI:107170 mgiHumanDisease false nextGxDx false ncbiReferenceSequences 301171653,301171668,530362356,301171661 refSeqAccessionIDs NG_011432.1 dermAtlas false hprdIDs 06100 swissProtIDs Q9Y2R2 zfinIDs ZDB-GENE-060503-458 uniGenes Hs.535276 gtr true cmgGene false ensemblIDs ENSG00000134242,ENST00000528414 umlsIDs C1419102 genbankNucleotideSequences 7688662,164692756,342906712,4100631,71515241,2910720,148123705,117606479,194381721,511869842,83565131,4689109,47938185,66257793,1572644,511869845,164693480,14970654,17389491,290765998 geneTests true approvedGeneSymbols PTPN22 geneIDs 26191 proteinSequences 7688663,20139861,4100632,301171669,342906713,530362357,194381722,119576977,4689110,47938186,117606480,119576978,1572645,119576979,224586929,119576980,290765999,17389492,301171662 geneticsHomeReferenceIDs gene;;PTPN22;;PTPN22

entryList

entry status live phenotypeMapList phenotypeMap geneSymbols APC, GS, FPC, BTPS2 sequenceID 4154 chromosomeLocationStart 112043201 chromosomeSort 296 phenotypeMimNumber 175100 chromosomeSymbol 5 mimNumber 611731 geneInheritance None phenotypeInheritance Autosomal dominant phenotypeMappingKey 3 phenotype Gardner syndrome computedCytoLocation 5q22.2 cytoLocation 5q22.2 transcript uc003kpy.4 chromosomeLocationEnd 112181935 chromosome 5 geneSymbols APC, GS, FPC, BTPS2 sequenceID 4154 chromosomeLocationStart 112043201 chromosomeSort 296 phenotypeMimNumber 175100 chromosomeSymbol 5 mimNumber 611731 geneInheritance None phenotypeInheritance Autosomal dominant phenotypeMappingKey 3 phenotype Brain tumor-polyposis syndrome 2 computedCytoLocation 5q22.2 cytoLocation 5q22.2 transcript uc003kpy.4 chromosomeLocationEnd 112181935 chromosome 5 geneSymbols APC, GS, FPC, BTPS2 sequenceID 4154 chromosomeLocationStart 112043201 chromosomeSort 296 phenotypeMimNumber 175100 chromosomeSymbol 5 mimNumber 611731 geneInheritance None phenotypeInheritance Autosomal dominant phenotypeMappingKey 3 phenotype Adenomatous polyposis coli computedCytoLocation 5q22.2 cytoLocation 5q22.2 transcript uc003kpy.4 chromosomeLocationEnd 112181935 chromosome 5 contributors Cassandra L. Kniffin - updated : 12/30/2008 Cassandra L. Kniffin - reorganized : 2/5/2008 externalLinks cmgGene false mgiHumanDisease true nextGxDx false omiaIDs 001916;;familial adenomatous polyposis coriellDiseases POL17510;;ADENOMATOUS POLYPOSIS OF THE COLON; APC nbkIDs NBK1345;;APC-Associated Polyposis Conditions dermAtlas false swissProtIDs P25054 gtr true possumSyndromes 6054;;Marfan-like habitus, familial adenomatous polyposis;;;3766;;Familial adenomatous polyposis umlsIDs C0162832,C0017097,C2674616,C2673218 orphanetDiseases 220460;;18912;;Attenuated familial adenomatous polyposis;;;99818;;14391;;Turcot syndrome with polyposis;;;79665;;11544;;Gardner syndrome;;;247806;;19550;;APC-related attenuated familial adenomatous polyposis;;;733;;105;;Familial adenomatous polyposis snomedctIDs 60876000 ordrDiseases 6482;;Gardner syndrome;;;6408;;Familial adenomatous polyposis;;;8532;;Attenuated FAP decipherUrls 5; FAP;;https://decipher.sanger.ac.uk/syndrome/49 geneTests false geneticAllianceIDs 2722 geneticsHomeReferenceIDs condition;;familial adenomatous polyposis;;familial-adenomatous-polyposis diseaseOntologyIDs 0050424 clinicalSynopsisExists true mimNumber 175100 dateCreated Mon, 02 Jun 1986 03:00:00 EDT clinicalSynopsis skinNailsHairSkinHistologyExists false headAndNeckEyesExists true headAndNeckMouthExists false genitourinaryBladderExists false skeletalSkullExists true neoplasia Adrenal carcinoma {SNOMEDCT:255035007} {UMLS:C1370740} {HPO HP:0006744 UMLS:C0206686,C1370740}; Thyroid papillary carcinoma {SNOMEDCT:4797003,255029007} {UMLS:C0238463} {HPO HP:0002895 UMLS:C0238463}; Periampullary carcinoma {UMLS:C0861830}; Fibrosarcoma {SNOMEDCT:53654007,443250000} {UMLS:C0016057} {HPO HP:0100244}; Colon carcinoma {SNOMEDCT:269533000} {UMLS:C0699790}; Gastric adenocarcinoma {SNOMEDCT:408647009} {UMLS:C0278701}; Medulloblastoma {UMLS:C2697367} {HPO HP:0002885 UMLS:C0025149}; Hepatoblastoma {SNOMEDCT:109843000,45024009} {ICD10CM:C22.2} {UMLS:C0206624} {HPO HP:0002884 UMLS:C0206624}; Small intestine carcinoid {UMLS:C1868072} {HPO HP:0006722 UMLS:C1868072}; Desmoid tumor {SNOMEDCT:399994005,47284001,400055004} {UMLS:C0079218}; Astrocytoma {SNOMEDCT:38713004} {UMLS:C0004114} {HPO HP:0009592 UMLS:C0004114} neurologicBehavioralPsychiatricManifestationsExists false molecularBasisExists true genitourinaryUretersExists false hematologyExists false creationDate John F. Jackson : 6/15/1995 prenatalManifestationsExists false cardiovascularHeartExists false dateCreated Thu, 15 Jun 1995 03:00:00 EDT cardiovascularExists false respiratoryExists false prenatalManifestationsPlacentaAndUmbilicalCordExists false dateUpdated Wed, 11 Apr 2012 03:00:00 EDT skeletalSpineExists false chestRibsSternumClaviclesAndScapulaeExists false abdomenPancreasExists false inheritanceExists true molecularBasis Caused by mutation in the adenomatous polyposis coli gene (APC, {611731.0001}) genitourinaryExists false abdomenBiliaryTractExists false prenatalManifestationsMovementExists false skeletalHandsExists false growthWeightExists false growthHeightExists false skinNailsHairHairExists false genitourinaryInternalGenitaliaFemaleExists false headAndNeckHeadExists false prenatalManifestationsDeliveryExists false oldFormatExists false abdomenGastrointestinal Multiple colonic adenomatous polyps {UMLS:C1868071} {HPO HP:0005227 UMLS:C1868071}; Multiple gastric polyps {SNOMEDCT:78809005,87252009} {UMLS:C0236048} {HPO HP:0004394 UMLS:C0236048}; Multiple duodenal polyps {UMLS:C0940442} {HPO HP:0004783 UMLS:C0940442}; Mesenteric fibromatosis {SNOMEDCT:45187003,400153009} {UMLS:C0206646} prenatalManifestationsAmnioticFluidExists false cardiovascularVascularExists false genitourinaryKidneysExists false skeletalLimbs Endosteal and exosteal osteomas {UMLS:C1868074} genitourinaryInternalGenitaliaMaleExists false abdomenLiverExists false headAndNeckFaceExists false chestExists true headAndNeckTeethExists true skeletalSkull Skull osteomas, especially involving the mandibular angle {UMLS:C1868073} skeletalPelvisExists false growthExists false abdomenGastrointestinalExists true voiceExists false skeletalExists true skeletalLimbsExists true laboratoryAbnormalitiesExists false miscellaneousExists true editHistory joanna : 04/11/2012 joanna : 8/15/2001 abdomenSpleenExists false respiratoryAirwaysExists false headAndNeckExists true neurologicExists false abdomenExists true skinNailsHairSkinElectronMicroscopyExists false headAndNeckEyes Congenital hypertrophy of retinal pigment epithelium (CHRPE) {SNOMEDCT:232074003} {UMLS:C0339555} {HPO HP:0007649} immunologyExists false skeletalFeetExists false headAndNeckEarsExists false respiratoryNasopharynxExists false neurologicPeripheralNervousSystemExists false neoplasiaExists true chestBreastsExists true headAndNeckTeeth Supernumerary teeth {SNOMEDCT:367534004,266414008} {ICD10CM:K00.1} {ICD9CM:520.1} {UMLS:C0040457} {HPO HP:0011069 UMLS:C0040457} {EOM ID:60888cccac8e54b6 IMG:Tooth,Supernumerary-small.jpg}; Unerupted teeth {SNOMEDCT:278658009} {UMLS:C0040458}; Dental caries {SNOMEDCT:80967001} {ICD10CM:K02,K02.9} {ICD9CM:521.0,521.00} {UMLS:C0011334} {HPO HP:0000670 UMLS:C0011334,C1867882}; Odontomas {SNOMEDCT:79074005} {UMLS:C0028882} {HPO HP:0011068} abdomenExternalFeaturesExists false respiratoryLarynxExists false skinNailsHairSkin Epidermoid inclusion cysts {UMLS:C1868075}; Fibromas {SNOMEDCT:112682009,424568000} {UMLS:C0016045}; Lipomas {SNOMEDCT:46720004,93163002} {ICD10CM:D17.9} {ICD9CM:214,214.9} {UMLS:C0023798} {HPO HP:0001012}; Lipofibromas {UMLS:C1868076}; Increased skin pigmentation {SNOMEDCT:4830009,49765009} {UMLS:C0162834} {HPO HP:0000953}; Keloids {SNOMEDCT:33659008,58405006} {ICD10CM:L91.0} {ICD9CM:701.4} {UMLS:C0022548} {HPO HP:0010562 UMLS:C0022548} contributors Kelly A. Przylepa - revised : 8/15/2001 skinNailsHairExists true chestDiaphragmExists false prenatalManifestationsMaternalExists false genitourinaryExternalGenitaliaFemaleExists false inheritance Autosomal dominant {SNOMEDCT:263681008} {UMLS:C0443147} {HPO HP:0000006 UMLS:C0443147} growthOtherExists false headAndNeckNeckExists false skinNailsHairNailsExists false neurologicCentralNervousSystemExists false genitourinaryExternalGenitaliaMaleExists false chestBreasts Mammary fibrosis {UMLS:C1868070} miscellaneous Prevalence 1 in 8000 {UMLS:C3277420}; Polyps occur in teens {UMLS:C1868079}; Colorectal cancer develops by fourth decade in untreated patients {UMLS:C1868080} respiratoryLungExists false metabolicFeaturesExists false skinNailsHairSkinExists true epochUpdated 1334127600 headAndNeckNoseExists false endocrineFeaturesExists false chestExternalFeaturesExists false muscleSoftTissueExists false epochCreated 803199600 prefix # titles alternativeTitles ADENOMATOUS POLYPOSIS OF THE COLON; APC;; FAMILIAL POLYPOSIS OF THE COLON; FPC;; POLYPOSIS, ADENOMATOUS INTESTINAL includedTitles GARDNER SYNDROME, INCLUDED; GS, INCLUDED;; BRAIN TUMOR-POLYPOSIS SYNDROME 2, INCLUDED; BTPS2, INCLUDED;; FAMILIAL ADENOMATOUS POLYPOSIS, ATTENUATED, INCLUDED; AFAP, INCLUDED;; ADENOMATOUS POLYPOSIS COLI, ATTENUATED, INCLUDED; AAPC, INCLUDED preferredTitle FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1 phenotypeMapExists true textSectionList textSection textSectionTitle Text textSectionContent A number sign (#) is used with this entry because familial adenomatous polyposis-1 (FAP1) and its variant Gardner syndrome are caused by heterozygous mutation in the APC gene ({611731}) on chromosome 5q22.2. See also hereditary desmoid disease ({135290}), an allelic disorder considered by some (e.g., {114:Lynch, 1996}) to be a variant of FAP. textSectionName text textSectionTitle Description textSectionContent Familial adenomatous polyposis is an autosomal dominant disorder characterized by predisposition to cancer. Affected individuals usually develop hundreds to thousands of adenomatous polyps of the colon and rectum, a small proportion of which will progress to colorectal carcinoma if not surgically treated. Gardner syndrome is a variant of FAP in which desmoid tumors, osteomas, and other neoplasms occur together with multiple adenomas of the colon and rectum ({136:Nishisho et al., 1991}). {155:Rustgi (2007)} reviewed the genetics of hereditary colon cancer, including APC. See also FAP2 ({608456}), a similar disorder showing autosomal recessive inheritance and caused by mutation in the MUTYH gene ({604933}) on chromosome 1p34. textSectionName description textSectionTitle Nomenclature textSectionContent Early terms for this disorder include multiple polyposis of the colon, hereditary polyposis coli, familial multiple polyposis, and familial polyposis of the colon (FPC). The designation familial adenomatous polyposis (FAP) is most often used today, particularly in Great Britain, based in part on the appreciation that the polyps are not confined to the colon. FAP has also been used as an acronym for familial amyloid polyneuropathy ({176300}) and for fibroblast activation protein ({600403}). textSectionName nomenclature textSectionTitle Clinical Features textSectionContent {57:Gardner (1951)} reported a large Utah family with intestinal polyposis that appeared to be a predisposing factor for carcinoma of the colon and rectum. Inheritance was autosomal dominant. In ensuing years, affected family members developed other abnormal growths, including intestinal polyps, osteomas, fibromas, and sebaceous cysts. Desmoid tumors, dental abnormalities, carcinoma of the ampulla of Vater, and thyroid carcinoma were also reported ({60:Gardner and Plenk, 1952}; {58:Gardner, 1962}). In a follow-up of this original family, {134:Naylor and Gardner (1977)} concluded that the mutant gene shows high penetrance and variable expressivity. {37:Danes and Gardner (1978)} noted that some branches of the original Utah family had the full syndrome, including both colonic and extracolonic lesions, whereas other branches had only extrabowel lesions. {68:Gorlin and Chaudhry (1960}) described familial association of multiple intestinal polyposis, multiple osteomata, fibromas, lipomas, and fibrosarcomas of the skin and mesentery, epidermoid inclusion cysts of the skin, and leiomyomas, and suggested that it was a heritable disorder of connective tissue. {158:Savage (1964)} reported a woman with Gardner syndrome who had multiple colorectal adenomas and rectal carcinoma, desmoid tumors, multiple sebaceous cysts, an osteoma of the forehead, and 2 subcutaneous lipomata. Although FAP patients with extracolonic features have been referred to in the past as having a distinct phenotype labeled 'Gardner syndrome,' detailed evaluation has shown that a majority of FAP patients have one or more extracolonic features ({103:Krush et al., 1988}). In addition, Gardner syndrome and FAP may occur in sibships, and both disorders are associated with pathologic mutations in the APC gene. Thus, Gardner syndrome is best described as a variant of FAP ({136:Nishisho et al., 1991}). {150:Pierce et al. (1970)} provided follow-up of a large Canadian kindred with FAP originally reported by {99:Kelly and McKinnon (1961)}. {150:Pierce et al. (1970)} concluded that the kindred actually had Gardner syndrome, which they referred to as a 'triad' of colonic polyposis, soft tissue abnormalities such as dermoid and epidermal cysts and desmoid tumors, and hard tissue abnormalities like osteomas. Of 71 affected family members, 37 had polyposis only, 10 had only soft tissue abnormalities, and 1 had only bone abnormalities. Nineteen family members manifested 2 components, and 4 had the complete triad. {18:Butson (1983)} reported a patient with FAP who had almost every recorded manifestation of the syndrome, including carcinomatous changes in the polyps, osteomas of facial and other bones, a periampullary carcinoma, transitional-cell carcinoma of the bladder, adrenal adenoma, and intraabdominal fibrous desmoid tumors with bowel obstruction. Lower Gastrointestinal Tract FAP is characterized by the development of hundreds of colorectal adenomas during adolescence. Colorectal cancer will develop in nearly all affected persons by the sixth decade of life if prophylactic colectomy is not performed ({66:Giardiello et al., 2002}). {3:Asman and Pierce (1970)} reported a large kindred from Kentucky with familial multiple polyposis of the intestine. No extraintestinal features were found. {167:Shull and Fitts (1974)} reported a family in which the father and 2 sons had both adenomatous and lymphoid polyps. {192:Venkitachalam et al. (1978)} pointed out that lymphoid polyposis had been reported several times in affected families. Upper Gastrointestinal Tract {161:Schnur et al. (1973)} reported the association of adenocarcinoma of the duodenum and Gardner syndrome. {49:Erbe and Welch (1978)} presented a patient with multiple polyps of the small bowel and 2 adenocarcinomas of the jejunum. {40:Denzler et al. (1979)} described 3 patients with FAP who also had adenomatous or hyperplastic polyps in the stomach and duodenum. The polyps were detected only by endoscopy or air-contrast radiographic examination. The findings suggested that gastric and duodenal polyps are more common in familial polyposis coli than previously recognized and should be considered an integral part of the syndrome. {176:Sugihara et al. (1982)} reported a 48-year-old man with Gardner syndrome and rectal carcinoma who developed a well-differentiated adenocarcinoma of the duodenum. Histologic examination showed a large adenoma with focal carcinoma, 256 adenomas of the duodenum, and 91 adenomas of the gastric antrum. A review of the literature showed 29 cases of periampullary carcinoma and 12 cases of gastric carcinoma complicating FAP or Gardner syndrome. Periampullary cancer is a well-recognized feature of FAP ({74:Harned and Williams, 1982}; {94:Jones and Nance, 1977}). The clustering of polyps around the ampulla of Vater implicates bile in the pathologic process ({144:Pauli et al., 1980}). {17:Burt et al. (1984)} found that 6 of 11 patients of the original Utah kindred reported by {57:Gardner (1951)} had numerous small polyps of the gastric fundus and body. Another patient had a single antral adenoma. Eight patients exhibited small duodenal adenomas, and 6 had ileal adenomas. The results indicated that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner syndrome. In a 26-year-old woman with Gardner syndrome, {194:Walsh et al. (1987)} found multifocal adenomatous change with severe dysplasia in the gallbladder. They referred to observations of others on bile duct cancer and carcinoma in situ of the gallbladder in patients with this form of hereditary polyposis. {90:Iida et al. (1988)} reviewed the natural history of gastric adenomas in FAP. Thirteen of 26 FAP patients were found to have gastric adenomas; during a 6.8-year follow-up, 6 of the 13 patients developed additional gastric adenomas. {138:Offerhaus et al. (1992)} commented on the fact that gastric cancer in Japan is more common than duodenal cancer in patients with FAP, and that gastric adenomas develop in 50% of Japanese patients with FAP. {92:Jagelman et al. (1988)} had observed that duodenal cancer was much more common than stomach cancer in Western APC gene carriers. {138:Offerhaus et al. (1992)} found that in the families in the Johns Hopkins Polyposis Registry, there was a greatly increased relative risk of duodenal adenocarcinoma and ampullary adenocarcinoma. No significant increased risk was found for gastric or nonduodenal small intestinal cancer. {5:Bapat et al. (1993)} stated that 24 to 96% of FAP patients develop periampullary adenomas. The authors identified 2 distinct somatic mutations in the APC gene ({611731.0019}; {611731.0020}) in 2 periampullary adenomas from an FAP patient. The findings were consistent with periampullary tumors being an extension of the same pathologic process. Congenital Hypertrophy of the Retinal Pigment Epithelium {11:Blair and Trempe (1980)} observed that congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a frequent finding in Gardner syndrome and can be a valuable clue to the presence of the gene in persons who have not yet developed other manifestations. The pigmented fundus lesion may be mistaken for malignant melanoma. {109:Lewis et al. (1984)} described multiple and bilateral patches of CHRPE in affected members of 3 families with Gardner syndrome. Most CHRPE lesions were unilateral, solitary, nonfamilial, and not known to be associated with other ocular or systemic disorders. The patches were 1 or 2 disc diameters in size with a surrounding area of depigmentation, and have been referred to as 'pigmented scars.' The center of the lesion showed chorioretinal atrophy and the peripheral hyperpigmentation. In 4 other families, a total of 8 patients did not show CHRPE. {15:Bull et al. (1985)} also reported observations on CHRPE in the Gardner syndrome. {183:Traboulsi et al. (1987)} examined 134 members of 16 families with Gardner syndrome for pigmented ocular fundus lesions. Of 41 patients with documented Gardner syndrome, 37 (90.2%) had such lesions. The lesions were bilateral in 32 of the patients and in 2 of 42 controls. Twenty (46.5%) of 43 first-degree relatives at 50% risk for Gardner syndrome had bilateral pigmented fundus lesions indicating that they probably had inherited the abnormal gene. The presence of bilateral lesions, multiple lesions (more than 4), or both appeared to be a specific (specificity = 0.952) and sensitive (sensitivity = 0.780) clinical marker for Gardner syndrome. Since the lesions were observed in a 3-month-old baby at risk, they were considered congenital. {43:Diaz-Llopis and Menezo (1988)} suggested that CHRPE may be a useful marker to detect patients at risk for FAP. Combining eye examination for CHRPE with data on age of onset and linked DNA markers appeared to be highly effective in carrier exclusion. {118:Lyons et al. (1988)} concluded that the CHRPE phenotype is a more powerful marker than other phenotypic features of Gardner syndrome. {4:Baker et al. (1988)} claimed that CHRPE is not as specific for Gardner syndrome compared to the presence of polyps. When ophthalmic examinations were performed on 56 at-risk patients, 8 patients were found to have the retinal lesions without any of the extracolonic features of Gardner syndrome. However, it was possible that the eye lesion may be the only extracolonic feature of Gardner syndrome. {26:Chapman et al. (1989)} searched for CHRPE in 40 patients representing all 25 pedigrees with FAP identified in the northern region of the U.K. All had multiple lesions, ranging in number from 2 to more than 40. None of 35 controls had more than 2 lesions. {85:Houlston et al. (1992)} suggested that CHRPE is not exclusively a manifestation of mutation at the APC locus. They described 3 patients who had 4 or more patches with no other extracolonic manifestations of FAP and all having fewer than 5 adenomatous polyps detected by colonoscopy. In the families of the 3 patients, a parent and the proband in each case had colorectal cancer. In 2 families, there was cancer of other types. {85:Houlston et al. (1992)} suggested that CHRPE can occur with cancer family syndromes. However, no search for mutations of the APC gene was made in these cases. Patients expressing CHRPE tend to cluster within specific polyposis families. CHRPE is traditionally regarded as a benign stationary condition. However, in at least 5 cases, CHRPE has given rise to elevated solid tumors ({164:Shields et al., 2000}). {163:Shields et al. (2001)} reported the histopathology of a progressively enlarging peripheral fundus tumor that arose from a focus of classic CHRPE. After removal of the mass by local resection, histopathologic examination revealed a low-grade adenocarcinoma of the retinal pigment epithelium, apparently arising from CHRPE. The authors concluded that CHRPE should be observed periodically for the development of neoplasm. Cutaneous and Skeletal Features {51:Fader et al. (1962)} first reported dental anomalies in Gardner syndrome. These include impacted teeth, supernumerary teeth, congenitally missing teeth, and abnormally long and pointed roots on the posterior teeth ({24:Carl and Herrera, 1987}). {93:Jarvinen et al. (1982)} found dental anomalies in 18% of patients, but jaw osteomata were very frequent. {82:Hoffmann and Brooke (1970)} described a family in which 6 persons in 3 generations had FAP and a mother and son had sarcoma of bone leading to death from metastases at 28 and 13 years of age, respectively. No evidence of polyposis was found in either but special studies including autopsies were not done. {185:Utsunomiya and Nakamura (1975)} recorded jaw osteomata, which appear as radiopaque lesions without a translucent halo, in 95% of FAP patients, but interpretation of the orthopantomograms is difficult and limits this as a diagnostic investigation. {69:Greer et al. (1977)} reported a patient with Gardner syndrome and chondrosarcoma of the hyoid bone. {20:Calin et al. (1999)} described 2 unrelated patients with FAP with unusual extracolonic phenotypes, namely several abnormalities of mesodermal origin strongly resembling Marfan syndrome (MFS; {154700}). One patient was a 28-year-old Romanian man who was unusually tall and thin, being 184 cm tall, compared to his father (165 cm tall), his mother (158 cm tall), and a brother and sister (168 and 161 cm tall, respectively). The patient's palate was narrow and high-arched with crowding of the teeth. There was moderate thoracic kyphoscoliosis, moderate hypermobility of all joints, and skin hyperextensibility. Moderate mental retardation was described. The second patient was a 38-year-old Romanian man who was 192 cm tall with arm span greater than height. An aortic diastolic murmur was heard. The diagnosis of FAP seemed well established in both patients; in the second patient the mother may have died at age 34 of FAP and a 36-year-old sister was found to have polyposis. Conventional cytogenetic and FISH analysis revealed no gross chromosomal rearrangement of 5q. In the second case, the FAP-causing mutation in the APC gene was found in the donor splice site of exon 4 and was shown to result in a frameshift and a premature termination codon. {20:Calin et al. (1999)} proposed that the connective tissue abnormalities resulted from germline APC mutations in combination with specific genetic and/or environmental modifying factors. Desmoid Tumors {168:Simpson et al. (1964)} reported the association of mesenteric fibromatosis in FAP and considered it to be a variant of Gardner syndrome. Mesenteric fibromatosis tended to develop after surgery. Also known as desmoid tumors, these slowly growing lesions were locally invasive and reached enormous proportions. {55:Fraumeni et al. (1968)} described a family in which the father and a daughter had a malignant mesenchymal tumor, a son had polyposis coli, and another son had both polyposis coli and malignant mesenchymal tumor. The authors also suggested that it was a variant of FAP. {101:Klemmer et al. (1987)} found an increased frequency of desmoids in patients with FAP. The crude frequency was about 6%, but the risk was dependent on age and sex. The lifetime risk was estimated to be 8% for males and 13% for females. {31:Clark et al. (1999)} reviewed the occurrence of desmoid tumor in FAP patients ascertained through a polyposis registry. They identified 166 desmoids in 88 patients; 83 tumors (50%) were within the abdomen, and 80 (48%) were in the abdominal wall. All but 16 individuals (18%) had already undergone abdominal surgery. Intraabdominal desmoids caused small bowel and ureteric obstruction and resulted in 10 deaths; survival was significantly poorer than in patients with abdominal wall desmoid alone, and 8 of 22 patients who underwent resection of intraabdominal desmoid died in the perioperative period. {31:Clark et al. (1999)} concluded that abdominal wall desmoids caused no deaths or significant morbidity; although recurrence was common after excision, the treatment was safe. They concluded that intraabdominal desmoids can cause serious complications, and treatment is often unsuccessful; in particular, surgery for desmoids at this site is hazardous. Hepatoblastoma {75:Heimann et al. (1987)} described a male patient who presented at 25 months of age with precocious puberty and an abdominal mass that was found to be a virilizing hepatoblastoma. {166:Shneider et al. (1992)} reported that the patient remained disease-free for 53 months following liver transplantation, but was found to have multiple adenomatous polyps of the colon at age 8 years. There was a strong maternal family history of polyposis and colon cancer. Ophthalmologic examination revealed CHRPE. Total colectomy and ileoanal reconstruction was performed when he was 10 years of age. Several groups noted the association of hepatoblastoma with polyposis coli (e.g., {100:Kingston et al., 1982}; {111:Li et al., 1987}; {103:Krush et al., 1988}). {111:Li et al. (1987)} observed hepatoblastoma in 4 unrelated children who had a family history of polyposis coli and found this association in 10 other kindreds in the literature. One child who survived hepatoblastoma showed multiple colonic adenomas at 7 years of age. She and 8 affected maternal relatives also had CHRPE. {103:Krush et al. (1988)} reported hepatoblastoma in 4 children from unrelated families. One child, 19 years old at the time of the report, survived after a resection of a hepatoblastoma in infancy and had recently been found to have Gardner syndrome. He, like many others in these 4 families, both affected and at risk, had osteomatous jaw lesions and pigmented ocular fundus lesions. In a worldwide collaborative study, {56:Garber et al. (1988)} identified 11 children with hepatoblastoma and a family history of adenomatous polyposis; 14 additional instances of the association were collected from the literature. Among the 11 survivors of hepatoblastoma in the combined series, adenomatous lesions of the colon had been sought in 7 and detected in 6 patients at ages 7 to 25 years. Five of these patients also had CHRPE. {64:Giardiello et al. (1991)} studied the frequency of hepatoblastoma in the families registered in the familial polyposis registry maintained at Johns Hopkins since 1973. Seven members of these families had hepatoblastoma diagnosed at ages varying from 1 month to 4.5 years. Six of them were from Gardner syndrome families and 1 was from a polyposis family without extrabowel manifestations. {64:Giardiello et al. (1991)} calculated the relative risk of hepatoblastoma in persons with the APC gene from birth through age 4 as being 3.3 per 1,000 person/years. In a retrospective review of their family history data, {87:Hughes and Michels (1992)} found that 2 of 470 (0.42%) children born to 241 patients with FAP had hepatoblastoma. This figure was significantly higher than the 1 in 100,000 incidence of hepatoblastoma in the general population. However, for genetic counseling purposes, an empiric risk of less than 1% for hepatoblastoma can be cited to persons with FAP for their children. Brain Tumor-Polyposis Syndrome 2 {33:Crail (1949)} reported a 24-year-old man with adenomatous polyposis, colonic adenocarcinoma, brainstem medulloblastoma, and papillary adenocarcinoma of the thyroid. {23:Capps et al. (1968)} described a family with 4 generations of polyposis and carcinoma of the colon. A brother of the proband died of brain tumor at age 9 years and had colonic polyposis. The proband, aged 14 years at first presentation, had carcinoma of the colon, ampulla of Vater, and urinary bladder. {72:Hamilton et al. (1995)} identified APC mutations (see, e.g., {175100.0014} and {175100.0022}) in 10 of 12 families with FAP in which at least 1 patient developed a central nervous system tumor, mainly medulloblastoma (79%), as an extracolonic manifestation of FAP. Since these index patients had both colonic polyposis and CNS tumors, they had originally been referred to as having Turcot syndrome (see {276300}). However, Turcot syndrome is usually considered an autosomal recessive disorder resulting from biallelic mutations in mismatch repair (MMR) genes (see, e.g., MLH1, {120436}); heterozygous mutations in MMR genes result in hereditary nonpolyposis colorectal cancer (HNPCC; see {120435}). {72:Hamilton et al. (1995)} estimated that the relative risk of medulloblastoma in FAP patients was 92 times greater than that found in the general population. Several of the patients with APC mutations also had pigmented ocular fundus lesions, epidermal inclusion cysts, or osteosclerotic jaw lesions consistent with Gardner syndrome. {143:Paraf et al. (1997)} proposed that Turcot syndrome, which they referred to as the 'brain tumor-polyposis (BTP) syndrome,' could be classified into 2 distinct entities. The authors referred to patients with mutations in mismatch repair genes as having 'BTP syndrome type 1' (BTPS1; {276300}). Patients from FAP kindreds with germline APC mutations who develop CNS tumors were referred to as having 'BTP syndrome type 2' (BTPS2). Risk analysis showed an increased incidence of medulloblastoma in FAP patients. By contrast, APC mutations were not found in sporadic glioma or medulloblastoma. In a review of reported FAP cases with medulloblastoma, {189:Van Meir (1998)} found that patients with medulloblastoma who also expressed the colorectal phenotype developed disease after age 17 years, whereas family members who did not express the colorectal phenotype had an age of brain tumor occurrence of less than 10 years. However, the authors noted that the young age of these patients may explain the absence of the colonic phenotype, which may have occurred at a later age. In a discussion of mechanism of inheritance, {189:Van Meir (1998)} suggested that the rarity of medulloblastoma in patients with FAP suggests the involvement of a second locus with a modifier gene or of environmental factors. Endocrine Carcinoma {22:Camiel et al. (1968)} described thyroid carcinoma in 2 sisters with Gardner syndrome, which was probably present in at least 3 generations of the family. {170:Smith (1968)} also described patients with the association of colonic polyps and papillary carcinoma of the thyroid. {78:Herve et al. (1995)} reported a case of papillary carcinoma in a 16-year-old girl with Gardner syndrome. They reviewed the literature and estimated that the incidence of thyroid carcinoma in patients with Gardner syndrome approached 100 times that of the general population. {21:Cameselle-Teijeiro and Chan (1999)} and {179:Tomoda et al. (2004)} noted that the papillary thyroid carcinoma most frequently associated with FAP is the distinctive cribriform-morular variant. {122:Marshall et al. (1967)} described a case of Gardner syndrome with adrenal cortical carcinoma with Cushing syndrome. In a member of the original Utah kindred with Gardner syndrome, {133:Naylor and Gardner (1981)} observed bilateral adrenal adenomas. They found reports of 6 cases of adrenal adenoma and 1 of primary adrenal carcinoma. They also reviewed 15 reported cases of thyroid tumors in Gardner syndrome. {7:Bell and Mazzaferri (1993)} reported what they alleged to represent the 37th report of the association of Gardner syndrome with papillary thyroid carcinoma. They pointed out that 94.3% of the patients have been women. {30:Chung et al. (2006)} described a 19-year-old woman with the cribriform-morular variant of papillary thyroid carcinoma, which had been discovered 8 months before the discovery of polyposis of the colon, in whom they identified a de novo R302X mutation ({175100.0006}). The authors noted that a hereditary colonic syndrome can be associated initially with an extracolonic tumor. Attenuated FAP {81:Hodgson et al. (1994)} suggested that heterozygous deletion of the entire APC gene may be associated with a form of FAP characterized by more proximal distribution of adenomas than usual, of which some are sessile and some may be nonpolypoid or flat. They postulated that in the usual type of FAP where the mutation results in a truncated protein, this protein may interfere with the function of the protein product of the normal allele to cause a more severe disease than seen in their patients. They pointed to the large kindreds reported by {107:Leppert et al. (1990)} and {117:Lynch et al. (1992)} as possible examples of this particular phenotype. {156:Samowitz et al. (1995)} pointed out that this seemingly different phenotype was referred to by {117:Lynch et al. (1992)} as 'hereditary flat adenoma syndrome.' Later, when it was found that the family reported by {107:Leppert et al. (1990)} and the families of {117:Lynch et al. (1992)} had characteristic mutations in the 5-prime end of the APC gene, the syndrome was renamed 'attenuated adenomatous polyposis coli' (AAPC). Attenuated adenomatous polyposis coli is characterized by the occurrence of less than 100 colonic adenomas and a later onset of colorectal cancer (age greater than 40 years) ({173:Soravia et al., 1998}). {50:Evans et al. (1993)} reported families with an attenuated form of FAP. In 1 family, a 59-year-old patient showed no abnormality; late onset of polyps was discovered by endoscopy and biopsy in other members of that family and in 2 other families. Mutation analysis in these families was not reported. {124:Matsumoto et al. (2002)} explored the possible association between serrated adenomas and FAP. Detailed colonoscopy and biopsy was undertaken in 11 individuals from 8 FAP families who had not undergone prophylactic colectomy. Serrated adenomas were detected in 3 individuals. Overall macroscopic polyp counts were less than 100 in these individuals. APC mutations were found in codons 161, 332, and 1556. These observations suggested that serrated adenomas may be an important feature of the attenuated form of FAP. textSectionName clinicalFeatures textSectionTitle Diagnosis textSectionContent {147:Petersen et al. (1989)} demonstrated how one could use linkage information to modify the genetic counseling recommendations for FAP. In the family of an affected 36-year-old man with a positive family history of FAP, there were 4 asymptomatic children under the age of 10 years. Before linkage analysis, all children had a 50% risk. The linkage information allowed a counselor to state to the family with 98% confidence that 3 of the children did not inherit the gene and that 1 child did. That child could be screened annually; the others could have screening every 3 years beginning at ages 12 or 13 and continuing until age 35. {182:Tops et al. (1989)} identified 2 linked polymorphic DNA markers on either side of the FAP locus. They estimated that use of these markers could allow prenatal and presymptomatic diagnosis with more than 99.9% reliability in most families. {45:Dunlop et al. (1990)} described 6 DNA markers flanking the APC gene that were useful for presymptomatic diagnosis. {46:Dunlop et al. (1991)} performed presymptomatic analysis of DNA from 41 individuals at risk for FAP. Of these, 28 individuals were informative, and 14 whose probe-derived risk was greater than 0.93 were subsequently demonstrated to be affected by clinical screening. The authors suggested that an integrated risk analysis, including genotypic, colonic, and ophthalmologic evaluation for the presence of CHRPE, should be used in FAP screening programs. {19:Cachon-Gonzalez et al. (1991)} concluded on the basis of linkage studies using 4 DNA probes that presymptomatic diagnosis could be given with only 90% probability based on DNA typing alone. {130:Morton et al. (1992)} demonstrated that DNA extracted from preserved tissue of dead relatives could be used to extend informativeness in FAP families. {146:Petersen et al. (1993)} demonstrated the feasibility of presymptomatic direct detection of APC mutations in each of 4 families. {120:Maher et al. (1993)} concluded that intragenic and closely linked DNA markers were informative in most families at risk for FAP and that the reduction in screening for low-risk relatives rendered molecular genetic diagnosis a cost-effective procedure. In their population-based study, they estimated a minimum heterozygote prevalence of 1/26,000. Of 33 probands, 8 (24%) represented new mutations. Interfamilial variation in CHRPE expression was evident, with ophthalmologic assessment showing more than 3 CHRPEs in 27 of 43 (63%) affected patients and high-risk relatives, and none of 18 low-risk relatives. {152:Powell et al. (1993)} developed a method based on the examination of APC proteins synthesized in vitro and study of endogenous APC transcripts, since most mutations in patients with FAP result in truncation of the APC gene product. In 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry, primary screening identified a truncated protein in 51 of the 62 patients (82%). In 3 of the 11 remaining patients, allele-specific expression assay demonstrated significantly reduced expression of one allele of the APC gene. Use of the 2 assays in combination successfully identified germline APC mutations in 87% of the 62 patients. A so-called 'protein truncation test,' based on the in vitro transcription and translation of genomic PCR products, was developed also by {186:van der Luijt et al. (1994)}. {142:Papadopoulos et al. (1995)} reported the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed monoallelic mutation analysis (MAMA). This simple and ingenious method involves the use of hamster/human somatic cell hybrids, which could be expected in many cases to have only 1 of the 2 alleles present. To show that single alleles were isolated in the clones, microsatellite markers proximal and distal to the gene of interest were assessed. {142:Papadopoulos et al. (1995)} demonstrated the utility of this strategy in FAP and in hereditary nonpolyposis cancer. {177:Thakker et al. (1995)} presented a weighted scoring system for changes on dental panoramic radiographs, called the Dental Panoramic Radiographs Score (DPRS), as a diagnostic tool for FAP. The score took into account the nature, extent, and sight of osseous and dental changes, as well as the incidence of the anomaly in the general population. Using the highest threshold, a specificity of 100% and sensitivity of approximately 68% were obtained. If all positive findings were considered as significant, sensitivity was increased to approximately 82%, but the specificity was reduced to approximately 88%. Overall, approximately 68% of the affected subjects had significant changes, and approximately 18% had normal appearance on DPR, with the remainder having changes classified as minimal or equivocal. The use of commercially available tests for genes linked to familial cancer is a source of concern about the possible adverse impact on patients. {62:Giardiello et al. (1997)} assessed indications for APC gene testing, through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. Of the 177 patients tested, 83% had clinical features of FAP or were at risk for the disease. Only 18.6% (33 of 177) received genetic counseling before the tests, and only 16.9% (28 of 166) provided written informed consent. In 31.6% of the cases, the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3% (1 of 44). {62:Giardiello et al. (1997)} concluded that physicians should be prepared to offer genetic counseling if they order genetic tests. {41:Deuter and Muller (1998)} described a highly sensitive and nonradioactive heteroduplex-PCR method (HD-PCR) for detecting APC mutations in stool DNA. {184:Traverso et al. (2002)} purified DNA from routinely collected stool samples and screened for APC mutations by a novel approach called digital protein truncation. Stool samples from 28 patients with nonmetastatic colorectal cancers, 18 patients with adenomas that were at least 1 cm in diameter, and 28 control patients without neoplastic disease were studied. APC mutations were identified in 26 of the 46 patients with neoplasia and in none of the 28 control patients. The authors emphasized, however, that their study had not established that the digital protein truncation test is a clinically useful screening procedure. textSectionName diagnosis textSectionTitle Clinical Management textSectionContent {193:Waddell and Loughry (1983)} were the first to make a connection between nonsteroidal antiinflammatory drugs (NSAIDs) and colon cancer. The authors observed the disappearance of rectal polyps in a patient with Gardner syndrome and correctly attributed this disappearance to treatment with sulindac, an NSAID that was given for unrelated reasons. In a random, double-blind, placebo-controlled study of 22 FAP patients, including 18 who had not undergone colectomy, {63:Giardiello et al. (1993)} found that oral sulindac reduced the number and size of colorectal adenomas. The effect was incomplete, however, leading the authors to conclude that it is unlikely to replace colectomy as primary therapy. {67:Giovannucci et al. (1994)} reported that patients who take aspirin or other NSAIDs on a regular basis have a 40 to 50% lower relative risk of colorectal cancer when compared with persons not regularly taking these medications. This effect has been confirmed in numerous clinical trials ({121:Marcus, 1995}), and the interpretation that NSAIDs promote regression of colon polyps by inhibiting prostaglandin synthesis has been supported by genetic studies in mice ({140:Oshima et al., 1996}). {160:Schnitzler et al. (1996)} demonstrated that sulindac inhibited the growth of carcinoma cells in vitro and caused an increase in APC mRNA. They suggested that the effect of these agents on colonic carcinogenesis was not mediated entirely via inhibition of prostaglandin biosynthesis. {77:Herrmann et al. (1998)} found that sulindac sulfide, the metabolite of sulindac, strongly inhibited Ras-induced malignant transformation. Sulindac sulfide decreased the Ras-induced activation of its main effector, the c-raf-1 kinase. {125:Maule (1994)} found that nurses could carry out screening by flexible sigmoidoscopy as accurately and safely as experienced gastroenterologists. However, {97:Kassirer (1994)}, while accepting the usefulness of many more nurse practitioners in collaborative practice arrangements, doubted that their function as entirely independent practitioners of primary care would be either cost-effective or safe. {174:Steinbach et al. (2000)} studied the effect of celecoxib, a selective COX2 inhibitor, on colorectal polyps in patients with FAP. In a double-blind, placebo-controlled study of 77 patients, they found that 6 months of twice-daily treatment with 400 mg of the agent significantly reduced the number of colorectal polyps. Using immunohistochemistry with activation-specific antibodies, {73:Hardwick et al. (2001)} demonstrated expression of COX2 and NFKB ({164011}) in stromal macrophages in human colonic adenomas. In addition, active JNK ({601158}) was expressed in stromal and intraepithelial T lymphocytes and periendothelial cells of new blood vessels. Active p38 (MAPK14; {600289}) was most highly expressed in stromal macrophages. {73:Hardwick et al. (2001)} concluded that active inflammatory signal transduction occurs predominantly in the stroma of colonic polyps. They suggested that NSAIDs may exert their chemopreventive effects in reducing colonic polyp size through effects on stromal rather than epithelial cells. {66:Giardiello et al. (2002)} reported that standard doses of sulindac did not prevent the development of adenomas in FAP patients. During 4 years of treatment, adenomas developed in 9 of 21 subjects (43%) in the sulindac group and in 11 of 20 subjects in the placebo group (55%). There was no significant difference in the mean number or size of polyps between the groups. Prophylactic colectomy remained the treatment of choice to prevent colorectal cancer in patients with this disorder. Despite the relatively disappointing results with respect to the ability of inhibition of cyclooxygenase to prevent adenomatous polyps in patients with FAP, {28:Chau and Cunningham (2002)} suggested that NSAIDs and cyclooxygenase-2 inhibitors may be shown to have a role in the primary prevention or treatment of established colorectal cancer. {123:Martinez et al. (2003)} studied the effect of an intronic polymorphism in the ornithine decarboxylase gene (ODC1; {165640.0001}) on the risk of recurrence of colorectal adenoma. They concluded that the ODC polymorphism and aspirin act independently to reduce the risk of adenoma recurrence by suppressing synthesis and activating catabolism, respectively, of colonic mucosal polyamines. Individuals homozygous for the minor OCD A allele who reported using aspirin were only one-tenth as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G allele. textSectionName clinicalManagement textSectionTitle Cytogenetics textSectionContent {76:Herrera et al. (1986)} found a constitutional interstitial deletion of 5q15-q22 in a man with possible Gardner syndrome; the large bowel was 'carpeted' with more than 100 adenomatous polyps and contained a well-differentiated carcinoma of the rectum, a similar carcinoma of the ascending colon, and melanosis coli. A small mesenteric neurofibroma was also found. In addition, the patient had severe mental retardation, horseshoe kidney, absence of the left lobe of the liver, and agenesis of the gallbladder. This finding of a deletion prompted the search for linkage with RFLP markers on 5q; positive results indicated that the mutation determining Gardner syndrome is located on 5q, probably near bands 5q21-q22. {102:Kobayashi et al. (1991)} described an interstitial deletion of 5q in a boy with Gardner syndrome who had mental retardation and multiple minor anomalies. The deletion involved q22.1-q31.1. Loss of constitutional heterozygosity (LOH) for markers on chromosome 5 is a frequent finding in colon cancers. {172:Solomon et al. (1987)} demonstrated that at least 20% of sporadic colorectal adenocarcinomas lose one of the alleles on chromosome 5q that is present in normal tissue of the host. {2:Ashton-Rickardt et al. (1989)} found that more than 50% of a large series of colorectal carcinomas had lost an allele near APC, suggesting that loss of the APC locus contributes to the malignant process. {79:Hockey et al. (1989)} described an interstitial deletion of 5q15-q22 in 2 intellectually handicapped brothers with familial adenomatous polyposis. Their retarded mother died of an inoperable carcinoma of the colon with extensive polyposis. Using probes linked to APC or chromosome 5, {139:Okamoto et al. (1990)} found a high incidence of allelic deletions among 51 colorectal tumors and 7 desmoids from 19 cases of FPC and 5 cases of Gardner syndrome, as well as 15 sporadic colon cancers. APC loss resulted primarily from interstitial deletion or mitotic recombination. Combined tumor and pedigree analysis in a Gardner syndrome family showed loss of normal 5q alleles in 3 tumors, including a desmoid tumor, which suggested the involvement of hemizygosity or homozygosity of the defective APC gene in colon carcinogenesis and possibly in extracolonic neoplasms. {34:Cross et al. (1992)} reported a male patient and his maternal aunt with Gardner syndrome and mental handicap who had an interstitial deletion of 5q22-q23.2, deleting the APC gene. Two other normal family members had the underlying direct insertion of of chromosome 5 (dir ins(5)(q31.3q22q23.2)). {34:Cross et al. (1992)} suggested that familial direct insertions should be considered as a cause of recurrent microdeletion syndromes. {80:Hodgson et al. (1993)} reported 2 cases of deletion of 5q associated with FAP. They noted that 5 such cases had previously been reported. In their 2 cases, as well as in one of those previously reported, macroscopic polyposis was confined to the proximal colon in patients in their thirties, although microscopic adenomatosis was shown in the more distal colon with occasional single polyps. Both of their subjects had dermoid cysts, and CHRPE was seen in one. The latter patient, who had the more extensive deletion, also showed Caroli disease (dilatation of distal intrahepatic bile ducts with intrahepatic stone formation); see {263200}. {6:Barber et al. (1994)} described an institutionalized adult woman who was referred for chromosome studies because of autistic behavior. A high risk of colorectal cancer was predicted when an interstitial deletion of 5q was found in lymphocytes and deletion of the MCC ({159350}) and APC genes confirmed by molecular analysis. Adenomatous polyposis coli and carcinoma of the rectum were subsequently diagnosed in the patient. The del(5)(q15q22.3) arose as a result of recombination within the small insertion loop formed at meiosis by the direct insertion found in the patient's mother. In a Dutch FAP family, {187:van der Luijt et al. (1995)} detected a germline rearrangement in the form of a constitutional reciprocal translocation t(5;10)(q22;q25), resulting in the disruption of the APC gene and an apparently null allele. The patients exhibited atypical clinical features, namely a slightly delayed age of onset of colorectal cancer and a reduced number of colorectal polyps that were mainly sessile and located predominantly in the proximal colon. This was thought to be the first description of a reciprocal translocation disrupting the APC gene. {39:De Chadarevian et al. (2002)} identified a constitutional inversion, inv(5)(q22-q31.3), associated with FAP in 3 generations of a Mexican family. The proband was a 16-month-old male with an 8-month history of liver masses, biopsies of which had been diagnosed as multiple adenomas. Liver transplantation was performed. His brother had died at almost 2 years of age following the resection of a tumor diagnosed as hepatoblastoma. Family history included a paternal grandfather who died of colon cancer. The child, his father, and a paternal uncle were found to carry the same constitutional inversion. Colonoscopy in the father demonstrated extensive colonic polyposis. Molecular analysis failed to demonstrate a truncated APC protein or an APC mutation, suggesting that the phenotype in this family may be the result of a position effect. textSectionName cytogenetics textSectionTitle Mapping textSectionContent By analysis of families with FAP, {12:Bodmer et al. (1987)} found linkage to marker C11p11 on chromosome 5q (maximum lod score of 3.26). The majority of the families studied were instances of Gardner syndrome, with extracolonic lesions such as epidermoid cysts, jaw osteomata, and fibrous desmoid tumors. The findings of {12:Bodmer et al. (1987)} suggested that Gardner syndrome and familial colorectal cancer are allelic disorders. In an accompanying paper, {172:Solomon et al. (1987)} demonstrated that at least 20% of sporadic colorectal adenocarcinomas lose one of the alleles on chromosome 5q that is present in normal tissue of the host. The findings suggested that a locus on 5q is critical for the progression of colorectal cancer. Simultaneously and independently, {108:Leppert et al. (1987)} demonstrated linkage of FAP in 5 families to a marker in the region of 5q22 (maximum lod score of 5.0). In 2 of the families, affected individuals had lesions typical of Gardner syndrome; in 3 families, it was typical of familial polyposis coli. Although most of the linkage information was provided by the families with the FAP phenotype, the findings indicated that Gardner syndrome and FAP are allelic disorders. Through studies in 6 families, {132:Nakamura et al. (1988)} refined the genetic localization of the polyposis locus to a position about 17 cM distal to the DNA probe C11p11 at 5q21-q22. Three of the families had the FAP phenotype and 3 had Gardner syndrome. In Dutch FAP kindreds, {127:Meera Khan et al. (1988)} found that the RFLP used by {12:Bodmer et al. (1987)} and {108:Leppert et al. (1987)} was minimally informative because of its low heterozygosity. On the other hand, another RFLP related to D5S37 and previously localized on 5q21 showed close linkage to FPC (lod = 7.85 at theta = 0.048 with 95% probability limits 0.005-0.145). The results were interpreted as indicating that the most likely location of the APC gene is in the band 5q22 very close to 5q21 or in the transitional zone between these 2 bands. By constructing human/hamster hybrid cell lines using cells from APC patients with deletions in the 5q15-q21 region, {190:Varesco et al. (1989)} identified 3 markers derived from CpG-rich islands that mapped within the deletions and were thus close to the APC gene. {104:Lasser et al. (1994)} studied a 2-generation, 12-member family in which 3 individuals, a father and a daughter and son by different mothers, had FAP and 2 sons by the second wife had colonic polyps and medulloblastomas. {104:Lasser et al. (1994)} stated that the brothers had 'Turcot syndrome;' however, analysis suggested linkage to the APC locus (lod score of 1.92 at marker D5S346), indicating that they had FAP and developed brain tumors, consistent with brain tumor-polyposis syndrome 2. textSectionName mapping textSectionTitle Molecular Genetics textSectionContent In 4 unrelated patients with familial adenomatous polyposis coli, {70:Groden et al. (1991)} identified 4 different heterozygous inactivating mutations in the APC gene ({611731.0001}-{611731.0004}). In the germline of 5 patients with FAP or Gardner syndrome, {136:Nishisho et al. (1991)} identified 4 point mutations in the APC gene ({611731.0005}-{611731.00008}) using both the ribonuclease (RNase) protection assay on PCR-amplified DNA and direct sequencing of cloned PCR products. One mutation ({611731.0006}) was found in 2 unrelated patients: 1 had adenomatous polyposis and the other had a desmoid tumor. {129:Miyoshi et al. (1992)} identified germline mutations in the APC gene in 53 (67%) of 79 unrelated FAP patients. Twenty-eight mutations were small deletions and 2 were insertions of 1 or 2 bp; 19 were point mutations resulting in stop codons, and 4 were missense point mutations. Thus, 92% of the mutations were predicted to result in truncation of the APC protein. More than two-thirds (68%) of the mutations were clustered in the 5-prime half of the last exon, and nearly two-fifths of the total mutations occurred at 1 of 5 positions. The findings suggested that the C terminal part of the protein is required for proper function. Using denaturing gradient gel electrophoresis (DGGE), {54:Fodde et al. (1992)} identified 8 different germline mutations in the APC gene (see, e.g., {611731.00012}-{611731.0018}) in Dutch patients with FAP. All the mutations resulted in truncated proteins. Modifier Genes {88:Humar et al. (2000)} performed mutation analysis in 130 members of an FAP family displaying strong phenotypic variation. None of the 3 common polymorphisms detected in the COX2 ({600262}) coding and promoter region segregated with a particular phenotype, and neither size nor quantity of COX2 transcript showed any correlation with disease expression in family members. The authors concluded that germline alterations in the COX2 gene are unlikely to account for the development of extracolonic disease in FAP patients. {151:Plasilova et al. (2004)} genotyped 50 members belonging to a large Swiss FAP kindred with extracolonic manifestations for 28 polymorphic markers spanning 58.7 cM of the 1p36-p32 region. Using 2-point linkage analysis, they found no evidence for the existence of a dominant modifier locus for extracolonic FAP disease. Mutation analysis of the candidate modifier gene MYH ({604933}) in all members of the family identified only a previously described V22M polymorphism in 1 unaffected and 2 affected members. {151:Plasilova et al. (2004)} thus excluded the 1p36-p33 region as a modifier locus and MYH as a modifier gene for extracolonic disease in this kindred. textSectionName molecularGenetics textSectionTitle Pathogenesis textSectionContent {86:Hsu et al. (1983)} found that the polyps of Gardner syndrome are multiclonal in origin, as are the tumors in neurofibromatosis (NF1; {162200}) and trichoepithelioma (CTLD1; {132700}). {153:Rasheed et al. (1983)} demonstrated that skin fibroblasts from patients with Gardner syndrome and familial polyposis coli showed increased susceptibility to retrovirus-induced transformation and chromosomal aneuploidy. {29:Chen et al. (1989)} concluded that the in vitro life span of cultured skin fibroblasts from individuals with FPC is markedly extended when compared with that of normal individuals. {13:Boland et al. (1995)} performed microallelotyping of many regions from individual colorectal tumors to determine the sequence and tempo of allelic loss at 5q, 17p, and 18q during neoplastic progression. No allelic losses were found in normal tissues surrounding colorectal neoplasms, but losses occurred abruptly on 5q at the transition from normal colonic epithelium to benign adenoma, and on 17p at the transition from adenoma to carcinoma, indicating an essential role for these losses in tumor progression. Allelic losses were uniform throughout extensively microdissected benign adenomas and carcinomas. However, substantial allelic heterogeneity was found in high-grade dysplasia, the transition lesion between adenoma and carcinoma. {13:Boland et al. (1995)} concluded that 5q (presumably APC) and 17p (presumably p53) are associated with abrupt waves of clonal neoplastic expansion. It is widely accepted that tumors are monoclonal in origin, arising from a mutation or series of mutations in a single cell and its descendants ({52:Fialkow, 1979}). Contradictory findings were reported by {137:Novelli et al. (1996)} who used direct in situ hybridization with Y chromosome probes to examine the clonal origin of colonic adenomas and uninvolved intestinal mucosa from an XO/XY mosaic individual with FAP. In this patient, the crypts of the small and large intestine were clonal, but at least 76% of the microadenomas were polyclonal in origin. Although other interpretations were considered, such as collision of separate tumors, {137:Novelli et al. (1996)} felt the results most strongly favored a true polyclonal nature of the polyps. By examining DNA replication errors in specific tumors, {83:Homfray et al. (1998)} found no evidence of mismatch repair defects occurring before APC mutations in the pathogenesis of sporadic colorectal tumors. The authors concluded that APC mutations, rather than genomic instability, are the initiating events in sporadic tumorigenesis. {116:Lynch and Smyrk (1998)} stated that multiple fundic gland polyps had preceded the finding of pathology in the colon in a relatively large number of their patients with attenuated FAP. The nature of desmoids in FAP is controversial, with arguments for and against a neoplastic origin. Neoplastic proliferations are by definition monoclonal, whereas reactive processes originate from a polyclonal background. {128:Middleton et al. (2000)} examined clonality of 25 samples of desmoid tissue from 11 female FAP patients by assessing patterns of X-chromosome inactivation to calculate a clonality ratio. PCR amplification of a polymorphic CAG short tandem repeat (STR) sequence adjacent to a methylation-sensitive restriction enzyme site within the human androgen receptor gene (AR; {313700}) was used. Twenty-one samples from 9 patients were informative for the assay. Samples from all informative cases comprised a median of 66% clonal cells. {128:Middleton et al. (2000)} concluded that FAP-associated desmoid tumors are true neoplasms. {165:Shih et al. (2001)} found that dysplastic cells at the tops of crypts of small colorectal adenomas contained APC alterations. In contrast, cell at the base of these same crypts did not contain APC alterations and were not clonally related to the transformed cells above. These findings implied that development of adenomatous polyps proceeds through a 'top-down' mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them. In a review of pathology reports from 44 individuals with FAP, {32:Crabtree et al. (2001)} found a correlation between adenoma:crypt ratio and macroscopic adenoma counts (r = 0.82, p less than 0.001) within individuals. There was no apparent variation in polyp density within a single colon at the microscopic level. There was also no detectable age-related increase in macroscopic adenoma count between sibs over the age range at which colectomies had been performed. The authors concluded that variation in disease severity was likely to result from different rates of tumor initiation rather than from differences in progression from microadenomas to macroscopic adenomas. The apparent lack of association between adenoma number and age suggested that most tumors may be initiated relatively early in a patient's life. {84:Houlston et al. (2001)} comprehensively reviewed mechanisms underlying phenotypic variability in individuals with FAP. See also 'APC Gene Function in Disease' in {611731}. textSectionName pathogenesis textSectionTitle Population Genetics textSectionContent In the Johns Hopkins Hospital Colon Polyposis Registry, established in 1973 and covering 6 states and the District of Columbia, 98 Gardner syndrome kindreds and 47 APC kindreds were recorded by April 1988. (The Peutz-Jeghers syndrome ({175200}) was registered in 19 kindreds.) {16:Burn et al. (1991)} estimated the prevalence of APC as 2.29 x 10(-5) in the northern region of England. {10:Bisgaard et al. (1994)} reported results based on a nationwide Danish polyposis registry that included all known Danish cases of FAP and their relatives. By identifying all FAP patients born between 1920 and 1949, they found the frequency of the disease to be 1 in 13,528. Disease penetrance for inherited cases was close to 100% by age 40 years. The mutation rate found by the direct method was 9 mutations per million gametes per generation, and the proportion of new mutants was estimated to be 25%. Fitness for patients between 15 and 29 years was found to be close to 1, while for patients older than 30 the fitness was reduced. Fitness increased over the 3 decades from date of birth (from 0.44 to 0.71), probably because treatment became more widespread and effective. When {10:Bisgaard et al. (1994)} used the overall fitness in the period, 0.87, to estimate the mutation rate by the indirect method, they found a lower value than by the direct method, namely, 5 mutations per million gametes per generation. {27:Charames et al. (2008)} identified a large heterozygous deletion in the APC promoter region in affected members of a large Canadian Mennonite kindred with adenomatous polyposis coli and colon cancer. The mutation was shown to result in transcriptional silencing of the APC allele. The findings were consistent with a founder effect in this genetically isolated population. textSectionName populationGenetics textSectionTitle History textSectionContent {59:Gardner (1972)} recounted the discovery of the Gardner syndrome. He was introduced to the large Utah family with colonic polyposis by a premedical student who was in his course in genetics in 1947. This family was the basis of the report on polyposis by {57:Gardner (1951)}. He also studied multiple osteomas and described the pattern of autosomal dominant inheritance and stated that 'as a working hypothesis the same gene is postulated to influence both abnormalities,' polyposis and osteomas ({60:Gardner and Plenk, 1952}). In the period 1950 to 1953, 4 kinds of abnormal growths (multiple intestinal polyposis, osteomas, fibromas, and sebaceous cysts) were observed in the same family members. Desmoid tumors, dental abnormalities, carcinoma of the ampulla of Vater, and thyroid carcinoma were later described. {171:Smith (1958)} observed desmoid tumors and postoperative scars in polyposis patients and initiated the designation 'Gardner syndrome.' {61:Gardner et al. (1982)} observed an excessive random loss and gain of single chromosomes in lymphocytes and fibroblasts cultured from patients with Gardner syndrome and familial polyposis coli and from children at risk for multiple adenomas in the colorectum. A consistent heteromorphism of chromosome 2, tentatively identified as a deletion, was observed in 17 patients with multiple colonic polyps and in 2 persons, aged 6 and 13 years, at risk for Gardner syndrome but as yet without colorectal polyps. The heteromorphism was not found in 2 patients with occasional discrete colorectal adenomas or in 18 controls without Gardner syndrome or familial polyposis coli. The portion of chromosome 2 affected was 2q14.3-q21.3. {53:Fineman et al. (1984)} did high resolution cytogenetic studies of mitotic chromosomes in peripheral blood of 2 patients with Gardner syndrome and 2 with familial polyposis; no deletion was found in chromosome 2. {98:Kasukawa et al. (1983)} also could find no abnormality of chromosome 2. {113:Luk and Baylin (1984)} concluded that the activity of ornithine decarboxylase ({165640}) may be a useful marker for the genotype of familial polyposis. This rate-limiting enzyme in the polyamine biosynthetic pathway is essential for intestinal mucosal proliferation. High levels of activity were found in normal-appearing colonic mucosa from 11 of 13 patients with familial polyposis and in all polyps biopsied from these same patients. Mucosa from dysplastic polyps showed higher mean ornithine decarboxylase activity than mucosa from polyps that were not dysplastic. Among clinically unaffected first-degree relatives of patients with familial polyposis, a bimodal distribution of ornithine decarboxylase activity was observed; one peak at the mean of normal controls and the other at the mean for normal-appearing mucosa from affected patients. In 40 Danish patients with familial polyposis coli, {141:Pandey et al. (1986)} found an increased frequency of Gm3;5;13. The 2 conditions could not be distinguished by this approach. {180:Tops et al. (1993)} described a family with seemingly typical autosomal dominant colonic polyposis, which was not linked to the APC locus. {175:Stella et al. (1993)} reported studies in 2 kindreds with a variant form of FAP: the number of colonic polyps was low and variable (from 5 to 100) and the disease showed a slower evolution than in the usual cases of FAP, with colon cancer occurring at a more advanced age in spite of early onset of intestinal manifestations. 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H. pubmedImages false title Familial multiple polyposis: a statistical study of a large Kentucky kindred. mimNumber 175100 referenceNumber 3 pubmedID 5443116 source Cancer 25: 972-981, 1970. authors Asman, H. B., Pierce, E. R. pubmedImages false title Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis. mimNumber 175100 referenceNumber 4 pubmedID 2852900 source Am. J. Med. Genet. 31: 427-435, 1988. authors Baker, R. H., Heinemann, M.-H., Miller, H. H., DeCosse, J. J. pubmedImages false articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8281160 publisherName HighWire Press title Identification of somatic APC gene mutations in periampullary adenomas in a patient with familial adenomatous polyposis (FAP). mimNumber 175100 referenceNumber 5 publisherAbbreviation HighWire pubmedID 8281160 source Hum. Molec. Genet. 2: 1957-1959, 1993. authors Bapat, B., Odze, R., Mitri, A., Berk, T., Ward, M., Gallinger, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8071957 publisherName HighWire Press title Adenomatous polyposis coli and a cytogenetic deletion of chromosome 5 resulting from a maternal intrachromosomal insertion. mimNumber 175100 referenceNumber 6 publisherAbbreviation HighWire pubmedID 8071957 source J. Med. Genet. 31: 312-316, 1994. authors Barber, J. C. K., Ellis, K. H., Bowles, L. V., Delhanty, J. D. A., Ede, R. F., Male, B. M., Eccles, D. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Familial adenomatous polyposis (Gardner's syndrome) and thyroid carcinoma: a case report and review of the literature. mimNumber 175100 referenceNumber 7 pubmedID 8420756 source Digest. Dis. Sci. 38: 185-190, 1993. authors Bell, B., Mazzaferri, E. L. pubmedImages false source Frankf. Z. Pathol. 42: 502-515, 1931. mimNumber 175100 authors Benecke, E. title Ueber Epitheliome auf Atheromen (Epidermoide) und Dermoidcysten der Haut. referenceNumber 8 title Familial polyposis and the role of the preventive registry. mimNumber 175100 referenceNumber 9 pubmedID 6113045 source Canad. Med. Assoc. J. 124: 1427-1428, 1981. authors Berk, T., Cohen, Z., Cullen, J. B. pubmedImages false title Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. mimNumber 175100 referenceNumber 10 pubmedID 8199592 source Hum. Mutat. 3: 121-125, 1994. authors Bisgaard, M. L., Fenger, K., Bulow, S., Niebuhr, E., Mohr, J. pubmedImages false title Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. mimNumber 175100 referenceNumber 11 pubmedID 7446647 source Am. J. Ophthal. 90: 661-667, 1980. authors Blair, N. P., Trempe, C. L. pubmedImages false articleUrl http://dx.doi.org/10.1038/328614a0 publisherName Nature Publishing Group title Localization of the gene for familial adenomatous polyposis on chromosome 5. mimNumber 175100 referenceNumber 12 publisherAbbreviation NPG pubmedID 3039373 source Nature 328: 614-616, 1987. authors Bodmer, W. F., Bailey, C. J., Bodmer, J., Bussey, H. J. R., Ellis, A., Gorman, P., Lucibello, F. C., Murday, V. A., Rider, S. H., Scambler, P., Sheer, D., Solomon, E., Spurr, N. K. pubmedImages false publisherUrl http://www.nature.com title Microallelotyping defines the sequence and tempo of allelic losses at tumour suppressor gene loci during colorectal cancer progression. mimNumber 175100 referenceNumber 13 pubmedID 7585215 source Nature Med. 1: 902-909, 1995. authors Boland, C. R., Sato, J., Appelman, H. D., Bresalier, R. S., Feinberg, A. P. pubmedImages false title Construction of a genetic linkage map in man using restriction fragment length polymorphisms. mimNumber 175100 referenceNumber 14 pubmedID 6247908 source Am. J. Hum. Genet. 32: 314-331, 1980. authors Botstein, D., White, R. L., Skolnick, M., Davis, R. W. pubmedImages false source Proc. Greenwood Genet. Center 4: 136 only, 1985. mimNumber 175100 authors Bull, M. J., Ellis, F. D., Sato, S., Weaver, D. D. title Hypertrophy of retinal pigment epithelium in Gardner syndrome. (Abstract) referenceNumber 15 articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1650842 publisherName HighWire Press title The UK northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations. mimNumber 175100 referenceNumber 16 publisherAbbreviation HighWire pubmedID 1650842 source J. Med. Genet. 28: 289-296, 1991. authors Burn, J., Chapman, P., Delhanty, J., Wood, C., Lalloo, F., Cachon-Gonzalez, M. B., Tsioupra, K., Church, W., Rhodes, M., Gunn, A. pubmedImages false publisherUrl http://highwire.stanford.edu title Upper gastrointestinal polyps in Gardner's syndrome. mimNumber 175100 referenceNumber 17 pubmedID 6690356 source Gastroenterology 86: 295-301, 1984. authors Burt, R. W., Berenson, M. M., Lee, R. G., Tolman, K. G., Freston, J. W., Gardner, E. J. pubmedImages false title Familial multiple polyposis coli with multiple associated tumors. mimNumber 175100 referenceNumber 18 pubmedID 6872787 source Dis. Colon Rectum 26: 578-582, 1983. authors Butson, A. R. C. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1658324 publisherName HighWire Press title Linkage analysis in adenomatous polyposis coli: the use of four closely linked DNA probes in 20 UK families. mimNumber 175100 referenceNumber 19 publisherAbbreviation HighWire pubmedID 1658324 source J. Med. Genet. 28: 681-685, 1991. authors Cachon-Gonzalez, M. B., Delhanty, J. D. A., Burn, J., Tsioupra, K., Davis, M. B., Attwood, J., Chapman, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200350 publisherName Nature Publishing Group title Marfan-like habitus and familial adenomatous polyposis in two unrelated males: a significant association? mimNumber 175100 referenceNumber 20 publisherAbbreviation NPG pubmedID 10439970 source Europ. J. Hum. Genet. 7: 609-614, 1999. authors Calin, G., Wijnen, J., van der Klift, H., Ionita, A., Mulder, A., Breukel, C., Smits, R., Dauwerse, H., Hansson, K., Calin, S., Stefanescu, D., Oproiu, A., Fodde, R. pubmedImages false publisherUrl http://www.nature.com source Mod. Path. 12: 400-411, 1999. mimNumber 175100 authors Cameselle-Teijeiro, J., Chan, J. K. C. title Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma? (Letter) referenceNumber 21 articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM196805092781908?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Association of thyroid carcinoma with Gardner's syndrome in siblings. mimNumber 175100 referenceNumber 22 publisherAbbreviation ATYPON pubmedID 5644968 source New Eng. J. Med. 278: 1056-1058, 1968. authors Camiel, M. R., Mule, J. E., Alexander, L. L., Benninghoff, D. L. pubmedImages false publisherUrl http://www.atypon.com/ title Carcinoma of the colon, ampulla of Vater and urinary bladder associated with familial multiple polyposis: a case report. mimNumber 175100 referenceNumber 23 pubmedID 5660235 source Dis. Colon Rectum 11: 298-304, 1968. authors Capps, W. F., Jr., Lewis, M. I., Gazzaniga, D. A. pubmedImages false source Sem. Surg. Oncol. 3: 77-83, 1987. mimNumber 175100 authors Carl, W., Herrera, L. title Dental and bone abnormalities in patients with familial polyposis coli. referenceNumber 24 title Bone abnormalities in Gardner's syndrome. mimNumber 175100 referenceNumber 25 pubmedID 5301730 source Am. J. Roentgen. 103: 645-652, 1968. authors Chang, C. H., Platt, E. D., Thomas, K. E., Watne, A. L. pubmedImages false title Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis. mimNumber 175100 referenceNumber 26 pubmedID 2538178 source Brit. Med. J. 298: 353-354, 1989. authors Chapman, P. D., Church, W., Burn, J., Gunn, A. pubmedImages false articleUrl http://dx.doi.org/10.1007/s00439-008-0579-4 publisherName Springer title A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred. mimNumber 175100 referenceNumber 27 publisherAbbreviation Springer pubmedID 18982352 source Hum. Genet. 124: 535-541, 2008. authors Charames, G. S., Ramyar, L., Mitri, A., Berk, T., Cheng, H., Jung, J., Bocangel, P., Chodirker, B., Greenberg, C., Spriggs, E., Bapat, B. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM200204043461412?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Cyclooxygenase inhibition in cancer - a blind alley or a new therapeutic reality? (Editorial) mimNumber 175100 referenceNumber 28 publisherAbbreviation ATYPON pubmedID 11932478 source New Eng. J. Med. 346: 1085-1087, 2002. authors Chau, I., Cunningham, D. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2538827 publisherName HighWire Press title Skin fibroblasts from individuals hemizygous for the familial adenopolyposis susceptibility gene show delayed crisis in vitro. mimNumber 175100 referenceNumber 29 publisherAbbreviation HighWire pubmedID 2538827 source Proc. Nat. Acad. Sci. 86: 2008-2012, 1989. authors Chen, S., Kazim, D., Kraveka, J., Pollack, R. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMcpc069028?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Case 37-2006: a 19-year-old woman with thyroid cancer and lower gastrointestinal bleeding. mimNumber 175100 referenceNumber 30 publisherAbbreviation ATYPON pubmedID 17135589 source New Eng. J. Med. 355: 2349-2357, 2006. authors Chung, D. C., Maher, M. M., Faquin, W. C. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1046/j.1365-2168.1999.01222.x publisherName John Wiley & Sons, Inc. title Desmoid tumours complicating familial adenomatous polyposis. mimNumber 175100 referenceNumber 31 publisherAbbreviation Wiley pubmedID 10504375 source Brit. J. Surg. 86: 1185-1189, 1999. authors Clark, S. K., Neale, K. F., Landgrebe, J. C., Phillips, R. K. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=11559652 publisherName HighWire Press title Variability in the severity of colonic disease in familial adenomatous polyposis results from differences in tumour initiation rather than progression and depends relatively little on patient age. mimNumber 175100 referenceNumber 32 publisherAbbreviation HighWire pubmedID 11559652 source Gut 49: 540-543, 2001. authors Crabtree, M. D., Tomlinson, I. P. M., Talbot, I. C., Phillips, R. K. S. pubmedImages false publisherUrl http://highwire.stanford.edu source U. S. Naval Med. Bull. 49: 123-128, 1949. mimNumber 175100 authors Crail, H. W. title Multiple primary malignancies arising in the rectum, brain, and thyroid: report of a case. referenceNumber 33 articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1313112 publisherName HighWire Press title An intrachromosomal insertion causing 5q22 deletion and familial adenomatous polyposis coli in two generations. mimNumber 175100 referenceNumber 34 publisherAbbreviation HighWire pubmedID 1313112 source J. Med. Genet. 29: 175-179, 1992. authors Cross, I., Delhanty, J., Chapman, P., Bowles, L. V., Griffin, D., Wolstenholme, J., Bradburn, M., Brown, J., Wood, C., Gunn, A., Burn, J. pubmedImages false publisherUrl http://highwire.stanford.edu title The Gardner syndrome. mimNumber 175100 referenceNumber 35 pubmedID 1212649 source Cancer 36: 2327-2333, 1975. authors Danes, B. S. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1271427 publisherName HighWire Press title The Gardner syndrome: increased tetraploidy in cultured skin fibroblast. mimNumber 175100 referenceNumber 36 publisherAbbreviation HighWire pubmedID 1271427 source J. Med. Genet. 13: 52-56, 1976. authors Danes, B. S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=739523 publisherName HighWire Press title The Gardner syndrome: a cell culture study of kindred 109. mimNumber 175100 referenceNumber 37 publisherAbbreviation HighWire pubmedID 739523 source J. Med. Genet. 15: 346-551, 1978. authors Danes, B. S., Gardner, E. J. pubmedImages false publisherUrl http://highwire.stanford.edu title Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. mimNumber 175100 referenceNumber 38 pubmedID 7485167 source Am. J. Hum. Genet. 57: 1151-1158, 1995. authors Davies, D. R., Armstrong, J. G., Thakker, N., Horner, K., Guy, S. P., Clancy, T., Sloan, P., Blair, V., Dodd, C., Warnes, T. W., Harris, R., Evans, D. G. R. pubmedImages false source Pediat. Dev. Path. 5: 69-75, 2002. mimNumber 175100 authors de Chadarevian, J.-P., Dunn, S., Malatack, J. J., Ganguly, A., Blecker, U., Punnett, H. H. title Chromosome rearrangement with no apparent gene mutation in familial adenomatous polyposis and hepatocellular neoplasia. referenceNumber 39 title Gastric polyps in familial polyposis coli. mimNumber 175100 referenceNumber 40 pubmedID 758668 source Radiology 130: 63-66, 1979. authors Denzler, T. B., Harned, R. K., Pergam, C. J. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1998)11:1<84::AID-HUMU13>3.0.CO;2-V publisherName John Wiley & Sons, Inc. title Detection of APC mutations in stool DNA of patients with colorectal cancer by HD-PCR. mimNumber 175100 referenceNumber 41 publisherAbbreviation Wiley pubmedID 9450908 source Hum. Mutat. 11: 84-89, 1998. authors Deuter, R., Muller, O. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Multiple polyposis coli associated with Gardner's syndrome and chromosomal mosaicism: a family analysis. mimNumber 175100 referenceNumber 42 pubmedID 2164769 source Am. J. Gastroenterol. 85: 880-883, 1990. authors Dhaliwal, M. K., Hughes, J. I., Jackson, G. L., Pathak, S. pubmedImages false articleUrl http://archopht.ama-assn.org/cgi/pmidlookup?view=long&pmid=2830869 publisherName HighWire Press title Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. mimNumber 175100 referenceNumber 43 publisherAbbreviation HighWire pubmedID 2830869 source Arch. Ophthal. 106: 412-413, 1988. authors Diaz-Llopis, M., Menezo, J. L. pubmedImages false publisherUrl http://highwire.stanford.edu title Etude mathematique de l'heredite de la polypose recto-colique. mimNumber 175100 referenceNumber 44 pubmedID 13724851 source J. Genet. Hum. 9: 65-77, 1960. authors Duhamel, J., Berthon, G., Dubarry, J. J. pubmedImages false title Genetic linkage map of six polymorphic DNA markers around the gene for familial adenomatous polyposis on chromosome 5. mimNumber 175100 referenceNumber 45 pubmedID 1978564 source Am. J. Hum. Genet. 47: 982-987, 1990. authors Dunlop, M. G., Wyllie, A. H., Nakamura, Y., Steel, C. M., Evans, H. J., White, R. L., Bird, C. C. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(91)90940-Q publisherName Elsevier Science title Linked DNA markers for presymptomatic diagnosis of familial adenomatous polyposis. mimNumber 175100 referenceNumber 46 publisherAbbreviation ES pubmedID 1671230 source Lancet 337: 313-316, 1991. authors Dunlop, M. G., Wyllie, A. H., Steel, C. M., Piris, J., Evans, H. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://adc.bmj.com/cgi/pmidlookup?view=long&pmid=9487968 publisherName HighWire Press title An unusually severe phenotype for familial adenomatous polyposis. mimNumber 175100 referenceNumber 47 publisherAbbreviation HighWire pubmedID 9487968 source Arch. Dis. Child. 77: 431-435, 1997. authors Eccles, D. M., Lunt, P. W., Wallis, Y., Griffiths, M., Sandhu, B., McKay, S., Morton, D., Shea-Simonds, J., Macdonald, F. pubmedImages false publisherUrl http://highwire.stanford.edu title Gardner syndrome and interstitial chromosome deletion. (Letter) mimNumber 175100 referenceNumber 48 pubmedID 2827476 source Am. J. Med. Genet. 28: 511-512, 1987. authors Endo, A., Kasukawa, T. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM197811302992208?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 47-1978. mimNumber 175100 referenceNumber 49 publisherAbbreviation ATYPON pubmedID 714081 source New Eng. J. Med. 299: 1237-1245, 1978. authors Erbe, R. W., Welch, W. R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=8244107 publisherName HighWire Press title Non-penetrance and late appearance of polyps in families with familial adenomatous polyposis. mimNumber 175100 referenceNumber 50 publisherAbbreviation HighWire pubmedID 8244107 source Gut 34: 1389-1393, 1993. authors Evans, D. G. R., Guy, S. P., Thakker, N., Armstrong, J. G., Dodd, C., Davies, D. R., Babbs, C., Clancy, T., Warnes, T., Sloan, P., Taylor, T. V., Harris, R. pubmedImages false publisherUrl http://highwire.stanford.edu title Gardner's syndrome (intestinal polyposis, osteomas, sebaceous cysts) and a new dental discovery. mimNumber 175100 referenceNumber 51 pubmedID 13891268 source Oral Surg. 15: 153-172, 1962. authors Fader, M., Kline, S. N., Spatz, S. S., Zubrow, H. J. pubmedImages false articleUrl http://arjournals.annualreviews.org/doi/full/10.1146/annurev.me.30.020179.001031?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Clonal origin of human tumors. mimNumber 175100 referenceNumber 52 publisherAbbreviation ATYPON pubmedID 400484 source Ann. Rev. Med. 30: 135-143, 1979. authors Fialkow, P. J. pubmedImages false publisherUrl http://www.atypon.com/ title Failure to demonstrate a chromosome 2 deletion in adenomatous colorectal polyposis patients. mimNumber 175100 referenceNumber 53 pubmedID 6690013 source Cancer 53: 317-318, 1984. authors Fineman, R. M., Morgan, M., Burt, R. W., Gardner, E. J. pubmedImages false title Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis. mimNumber 175100 referenceNumber 54 pubmedID 1324223 source Genomics 13: 1162-1168, 1992. authors Fodde, R., van der Luijt, R., Wijnen, J., Tops, C., van der Klift, H., van Leeuwen-Cornelisse, I., Griffioen, G., Vasen, H., Meera Khan, P. pubmedImages false articleUrl http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=4383807 publisherName HighWire Press title Sarcomas and multiple polyposis in a kindred. A genetic variety of hereditary polyposis? mimNumber 175100 referenceNumber 55 publisherAbbreviation HighWire pubmedID 4383807 source Arch. Intern. Med. 121: 57-61, 1968. authors Fraumeni, J. F., Jr., Vogel, C. L., Easton, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2848134 publisherName HighWire Press title Hepatoblastoma and familial adenomatous polyposis. mimNumber 175100 referenceNumber 56 publisherAbbreviation HighWire pubmedID 2848134 source J. Nat. Cancer Inst. 80: 1626-1628, 1988. Note: Erratum: J. Nat. Cancer Inst. 81: 461 only, 1989. authors Garber, J. E., Li, F. P., Kingston, J. E., Krush, A. J., Strong, L. C., Finegold, M. J., Bertario, L., Bulow, S., Filippone, A., Jr., Gedde-Dahl, T., Jr., Jarvinen, H. J. pubmedImages false publisherUrl http://highwire.stanford.edu title A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. mimNumber 175100 referenceNumber 57 pubmedID 14902760 source Am. J. Hum. Genet. 3: 167-176, 1951. authors Gardner, E. J. pubmedImages false title Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. mimNumber 175100 referenceNumber 58 pubmedID 13946545 source Am. J. Hum. Genet. 14: 376-390, 1962. authors Gardner, E. J. pubmedImages false source Birth Defects Orig. Art. Ser. VIII(2): 48-51, 1972. mimNumber 175100 authors Gardner, E. J. title Discovery of the Gardner syndrome. referenceNumber 59 title Hereditary pattern for multiple osteomas in a family group. mimNumber 175100 referenceNumber 60 pubmedID 14933371 source Am. J. Hum. Genet. 4: 31-36, 1952. authors Gardner, E. J., Plenk, H. P. pubmedImages false title Numerical and structural chromosome aberrations in cultured lymphocytes and cutaneous fibroblasts of patients with multiple adenomas of the colorectum. mimNumber 175100 referenceNumber 61 pubmedID 7059954 source Cancer 49: 1413-1419, 1982. authors Gardner, E. J., Rogers, S. W., Woodward, S. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199703203361202?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. mimNumber 175100 referenceNumber 62 publisherAbbreviation ATYPON pubmedID 9062090 source New Eng. J. Med. 336: 823-827, 1997. authors Giardiello, F. M., Brensinger, J. D., Petersen, G. M., Luce, M. C., Hylind, L. M., Bacon, J. A., Booker, S. V., Parker, R. D., Hamilton, S. R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199305063281805?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. mimNumber 175100 referenceNumber 63 publisherAbbreviation ATYPON pubmedID 8385741 source New Eng. J. Med. 328: 1313-1316, 1993. authors Giardiello, F. M., Hamilton, S. R., Krush, A. J., Piantadosi, S., Hylind, L. M., Celano, P., Booker, S. V., Robinson, C. R., Offerhaus, G. J. A. pubmedImages false publisherUrl http://www.atypon.com/ title Risk of hepatoblastoma in familial adenomatous polyposis. mimNumber 175100 referenceNumber 64 pubmedID 1658283 source J. Pediat. 119: 766-768, 1991. authors Giardiello, F. M., Offerhaus, G. J. A., Krush, A. J., Booker, S. V., Tersmette, A. C., Mulder, J.-W. R., Kelley, C. N., Hamilton, S. R. pubmedImages false articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=9176082 publisherName HighWire Press title APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. mimNumber 175100 referenceNumber 65 publisherAbbreviation HighWire pubmedID 9176082 source Gut 40: 521-525, 1997. authors Giardiello, F. M., Petersen, G. M., Piantadosi, S., Gruber, S. B., Traboulsi, E. I., Offerhaus, G. J. A., Muro, K., Krush, A. J., Booker, S. V., Luce, M. C., Laken, S. J., Kinzler, K. W., Vogelstein, B., Hamilton, S. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa012015?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Primary chemoprevention of familial adenomatous polyposis with sulindac. mimNumber 175100 referenceNumber 66 publisherAbbreviation ATYPON pubmedID 11932472 source New Eng. J. Med. 346: 1054-1059, 2002. authors Giardiello, F. M., Yang, V. W., Hylind, L. M., Krush, A. J., Petersen, G. M., Trimbath, J. D., Piantadosi, S., Garrett, E., Geiman, D. E., Hubbard, W., Offerhaus, G. J. A., Hamilton, S. R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.annals.org/cgi/pmidlookup?view=long&pmid=8037405 publisherName HighWire Press title Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. mimNumber 175100 referenceNumber 67 publisherAbbreviation HighWire pubmedID 8037405 source Ann. Intern. Med. 121: 241-246, 1994. authors Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A., Ascherio, A., Willett, W. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM196012082632301?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Multiple osteomatosis, fibromas, lipomas and fibrosarcomas of the skin and mesentery, epidermoid inclusion cysts of the skin, leiomyomas and multiple intestinal polyposis: an heritable disorder of connective tissue. mimNumber 175100 referenceNumber 68 publisherAbbreviation ATYPON pubmedID 13707264 source New Eng. J. Med. 263: 1151-1158, 1960. authors Gorlin, R. J., Chaudhry, A. P. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://archotol.ama-assn.org/cgi/pmidlookup?view=long&pmid=880110 publisherName HighWire Press title Gardner's syndrome and chondrosarcoma of the hyoid bone. mimNumber 175100 referenceNumber 69 publisherAbbreviation HighWire pubmedID 880110 source Arch. Otolaryng. 103: 425-427, 1977. authors Greer, J. A., Jr., Devine, K. D., Dahlin, D. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0092-8674(81)90021-0 publisherName Elsevier Science title Identification and characterization of the familial adenomatous polyposis coli gene. mimNumber 175100 referenceNumber 70 publisherAbbreviation ES pubmedID 1651174 source Cell 66: 589-600, 1991. authors Groden, J., Thliveris, A., Samowitz, W., Carlson, M., Gelbert, L., Albertsen, H., Joslyn, G., Stevens, J., Spirio, L., Robertson, M., Sargeant, L., Krapcho, K., Wolff, E., Burt, R., Hughes, J. P., Warrington, J., McPherson, J., Wasmuth, J., Le Paslier, D., Abderrahim, H., Cohen, D., Leppert, M., White, R. pubmedImages false publisherUrl http://www.elsevier.com/ title Bilateral fibromatosis of the breast in Gardner's syndrome. mimNumber 175100 referenceNumber 71 pubmedID 5410306 source Cancer 25: 161-166, 1970. authors Haggitt, R. C., Booth, J. L. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199503303321302?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title The molecular basis of Turcot's syndrome. mimNumber 175100 referenceNumber 72 publisherAbbreviation ATYPON pubmedID 7661930 source New Eng. J. Med. 332: 839-847, 1995. authors Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1038/sj.onc.1204162 publisherName Nature Publishing Group title NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. mimNumber 175100 referenceNumber 73 publisherAbbreviation NPG pubmedID 11314016 source Oncogene 20: 819-827, 2001. authors Hardwick, J. C. H., van den Brink, G. R., Offerhaus, G. J., van Deventer, S. J. H., Peppelenbosch, M. P. pubmedImages false publisherUrl http://www.nature.com title Familial polyposis coli and periampullary malignancy. mimNumber 175100 referenceNumber 74 pubmedID 7067564 source Dis. Colon Rectum 25: 227-229, 1982. authors Harned, R. K., Williams, S. M. pubmedImages false title Hepatoblastoma presenting as isosexual precocity: the clinical importance of histologic and serologic parameters. mimNumber 175100 referenceNumber 75 pubmedID 2435780 source J. Clin. Gastroent. 9: 105-110, 1987. authors Heimann, A., White, P. F., Riely, C. A., Ritchey, A. K., Flye, M. W., Barwick, K. W. pubmedImages false title Gardner syndrome in a man with an interstitial deletion of 5q. mimNumber 175100 referenceNumber 76 pubmedID 3789010 source Am. J. Med. Genet. 25: 473-476, 1986. authors Herrera, L., Kakati, S., Gibas, L., Pietrzak, E., Sandberg, A. A. pubmedImages false articleUrl http://dx.doi.org/ publisherName Nature Publishing Group title Sulindac sulfide inhibits Ras signaling. mimNumber 175100 referenceNumber 77 publisherAbbreviation NPG pubmedID 9778042 source Oncogene 17: 1769-1776, 1998. authors Herrmann, C., Block, C., Geisen, C., Haas, K., Weber, C., Winde, G., Moroy, T., Muller, O. pubmedImages false publisherUrl http://www.nature.com title Association syndrome de Gardner et carcinome thyroidien. (Letter) mimNumber 175100 referenceNumber 78 pubmedID 7899423 source Presse Med. 24: 415 only, 1995. authors Herve, R., Farret, O., Mayaudon, H., Helie, C., Denee, J. M., Bauduceau, B., Molinie, C. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=2537430 publisherName HighWire Press title Deletion of chromosome 5q and familial adenomatous polyposis. mimNumber 175100 referenceNumber 79 publisherAbbreviation HighWire pubmedID 2537430 source J. Med. Genet. 26: 61-62, 1989. authors Hockey, K. A., Mulcahy, M. T., Montgomery, P., Levitt, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8391580 publisherName HighWire Press title Two cases of 5q deletions in patients with familial adenomatous polyposis: possible link with Caroli's disease. mimNumber 175100 referenceNumber 80 publisherAbbreviation HighWire pubmedID 8391580 source J. Med. Genet. 30: 369-375, 1993. authors Hodgson, S. V., Coonar, A. S., Hanson, P. J. V., Cottrell, S., Scriven, P. N., Jones, T., Hawley, P. R., Wilkinson, M. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8064829 publisherName HighWire Press title Deletions of the entire APC gene are associated with sessile colonic adenomas. (Letter) mimNumber 175100 referenceNumber 81 publisherAbbreviation HighWire pubmedID 8064829 source J. Med. Genet. 31: 426 only, 1994. authors Hodgson, S. V., Fagg, N. L. K., Talbot, I. C., Wilkinson, M. pubmedImages false publisherUrl http://highwire.stanford.edu title Familial sarcoma of bone in a polyposis coli family. mimNumber 175100 referenceNumber 82 pubmedID 5441862 source Dis. Colon Rectum 13: 119-120, 1970. authors Hoffmann, D. C., Brooke, B. N. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1998)11:2<114::AID-HUMU3>3.0.CO;2-J publisherName John Wiley & Sons, Inc. title Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours. mimNumber 175100 referenceNumber 83 publisherAbbreviation Wiley pubmedID 9482574 source Hum. Mutat. 11: 114-120, 1998. authors Homfray, T. F. R., Cottrell, S. E., Ilyas, M., Rowan, A., Talbot, I. C., Bodmer, W. F., Tomlinson, I. P. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=11115811 publisherName HighWire Press title Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes. mimNumber 175100 referenceNumber 84 publisherAbbreviation HighWire pubmedID 11115811 source Gut 48: 1-5, 2001. authors Houlston, R., Crabtree, M., Phillips, R., Crabtree, M., Tomlinson, I. pubmedImages false publisherUrl http://highwire.stanford.edu title Congenital hypertrophy of retinal pigment epithelium in patients with colonic polyps associated with cancer family syndrome. mimNumber 175100 referenceNumber 85 pubmedID 1325301 source Clin. Genet. 42: 16-18, 1992. authors Houlston, R. S., Fallon, T., Harocopos, C., Williams, C. B., Davey, C., Slack, J. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6879192 publisherName HighWire Press title Multiclonal origin of polyps in Gardner syndrome. mimNumber 175100 referenceNumber 86 publisherAbbreviation HighWire pubmedID 6879192 source Science 221: 951-953, 1983. authors Hsu, S. H., Luk, G. D., Krush, A. J., Hamilton, S. R., Hoover, H. H., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu title Risk of hepatoblastoma in familial adenomatous polyposis. mimNumber 175100 referenceNumber 87 pubmedID 1329510 source Am. J. Med. Genet. 43: 1023-1025, 1992. authors Hughes, L. J., Michels, V. V. pubmedImages false articleUrl http://dx.doi.org/10.1002/1097-0215(20000915)87:6<812::AID-IJC9>3.0.CO;2-A publisherName John Wiley & Sons, Inc. title Germline alterations in the cyclooxygenase-2 gene are not associated with the development of extracolonic manifestations in a large Swiss familial adenomatous polyposis kindred. mimNumber 175100 referenceNumber 88 publisherAbbreviation Wiley pubmedID 10956391 source Int. J. Cancer 87: 812-817, 2000. authors Humar, B., Giovanoli, O., Wolf, A., Attenhofer, M., Bendik, I., Meier, R., Muller, H., Dobbie, Z. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Familial gastric polyposis (cont.) (Letter) mimNumber 175100 referenceNumber 89 pubmedID 958301 source New Eng. J. Med. 295: 905 only, 1976. authors Hyson, E. A., Burrell, M. pubmedImages false title Natural history of gastric adenomas in patients with familial adenomatosis coli/Gardner's syndrome. mimNumber 175100 referenceNumber 90 pubmedID 3338026 source Cancer 61: 605-611, 1988. authors Iida, M., Yao, T., Itoh, H., Watanabe, H., Matsui, T., Iwashita, A., Fujishima, M. pubmedImages false title Hereditary sebaceous cysts. mimNumber 175100 referenceNumber 91 pubmedID 20780649 source Brit. Med. J. 1: 960-963, 1937. authors Ingram, J. T., Oldfield, M. C. pubmedImages false title Upper gastrointestinal cancer in familial adenomatous polyposis. mimNumber 175100 referenceNumber 92 pubmedID 2896968 source Lancet 331: 1149-1151, 1988. Note: Originally Volume I. authors Jagelman, D. G., DeCosse, J. J., Bussey, H. J. R., {the Leeds Castle Polyposis Group} pubmedImages false title Gardner's stigmas in patients with familial adenomatosis coli. mimNumber 175100 referenceNumber 93 pubmedID 6129019 source Brit. J. Surg. 69: 718-721, 1982. authors Jarvinen, H. J., Peltokallio, P., Landtman, M., Wolf, J. pubmedImages false title Periampullary malignancy in Gardner's syndrome. mimNumber 175100 referenceNumber 94 pubmedID 856075 source Ann. Surg. 185: 565-573, 1977. authors Jones, T. R., Nance, F. C. pubmedImages false title Familial T-cell lymphoblastic lymphoma: association with von Recklinghausen neurofibromatosis and Gardner syndrome. mimNumber 175100 referenceNumber 95 pubmedID 6805315 source Am. J. Hemat. 12: 247-250, 1982. authors Kaplan, J., Cushing, B., Chang, C.-H., Poland, R., Roscamp, J., Perrin, E., Bhaya, N. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=9950370 publisherName HighWire Press title Familial adenomatous polyposis associated with multiple adrenal adenomas in a patient with a rare 3-prime APC mutation. mimNumber 175100 referenceNumber 96 publisherAbbreviation HighWire pubmedID 9950370 source J. Med. Genet. 36: 65-67, 1999. authors Kartheuser, A., Walon, C., West, S., Breukel, C., Detry, R., Gribomont, A.-C., Hamzehloei, T., Hoang, P., Maiter, D., Pringot, J., Rahier, J., Khan, P. M., Curtis, A., Burn, J., Fodde, R., Verellen-Dumoulin, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199401203300310?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title What role for nurse practitioner in primary care? (Editorial) mimNumber 175100 referenceNumber 97 publisherAbbreviation ATYPON pubmedID 8204151 source New Eng. J. Med. 330: 204-205, 1994. authors Kassirer, J. P. pubmedImages false publisherUrl http://www.atypon.com/ source Cancer Genet. Cytogenet. 9: 283-295, 1983. mimNumber 175100 authors Kasukawa, T., Watanabe, T., Endo, A. title Absence of heteromorphism of chromosome number 2 homologues in patients with hereditary adenomatosis of the colon and rectum. referenceNumber 98 title Familial multiple polyposis of the colon: review and description of a large kindred. mimNumber 175100 referenceNumber 99 pubmedID 13752393 source McGill Med. J. 30: 67-85, 1961. authors Kelly, P. B., McKinnon, D. A. pubmedImages false title Hepatoblastoma and polyposis coli. (Letter) mimNumber 175100 referenceNumber 100 pubmedID 6121129 source Lancet 319: 457 only, 1982. Note: Originally Volume 1. authors Kingston, J. E., Draper, G. J., Mann, J. R. pubmedImages false title Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. mimNumber 175100 referenceNumber 101 pubmedID 2827474 source Am. J. Med. Genet. 28: 385-392, 1987. authors Klemmer, S., Pascoe, L., DeCosse, J. pubmedImages false title Gardner syndrome in a boy with interstitial deletion of the long arm of chromosome 5. mimNumber 175100 referenceNumber 102 pubmedID 1776638 source Am. J. Med. Genet. 41: 460-463, 1991. authors Kobayashi, T., Narahara, K., Yokoyama, Y., Ueyama, S., Mohri, O., Fujii, T., Fujimoto, M., Ohtsuki, S., Tsuji, K., Seino, Y. pubmedImages false title Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome. mimNumber 175100 referenceNumber 103 pubmedID 3354603 source Am. J. Med. Genet. 29: 323-332, 1988. authors Krush, A. J., Traboulsi, E. I., Offerhaus, G. J. A., Maumenee, I. H., Yardley, J. H., Levin, L. S. pubmedImages false title Turcot's syndrome: evidence for linkage to the adenomatous polyposis coli (APC) locus. mimNumber 175100 referenceNumber 104 pubmedID 8208405 source Neurology 44: 1083-1086, 1994. authors Lasser, D. M., DeVivo, D. C., Garvin, J., Wilhelmsen, K. C. pubmedImages false title Familial polyposis coli in Black patients. mimNumber 175100 referenceNumber 105 pubmedID 889375 source Ann. Surg. 186: 324-333, 1977. authors Leffall, L. D., Chung, E. B., Dewitty, R. L., Cornwell, E. E., Blakey, T. M. pubmedImages false title Epidermoid cysts, polyposis coli and Gardner's syndrome. mimNumber 175100 referenceNumber 106 pubmedID 1139135 source Brit. J. Surg. 62: 387-393, 1975. authors Leppard, B., Bussey, H. J. R. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199003293221306?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. mimNumber 175100 referenceNumber 107 publisherAbbreviation ATYPON pubmedID 2156161 source New Eng. J. Med. 322: 904-908, 1990. authors Leppert, M., Burt, R., Hughes, J. P., Samowitz, W., Nakamura, Y., Woodward, S., Gardner, E., Lalouel, J.-M., White, R. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=3479843 publisherName HighWire Press title The gene for familial polyposis coli maps to the long arm of chromosome 5. mimNumber 175100 referenceNumber 108 publisherAbbreviation HighWire pubmedID 3479843 source Science 238: 1411-1413, 1987. authors Leppert, M., Dobbs, M., Scambler, P., O'Connell, P., Nakamura, Y., Stauffer, D., Woodward, S., Burt, R., Hughes, J., Gardner, E., Lathrop, M., Wasmuth, J., Lalouel, J.-M., White, R. pubmedImages false publisherUrl http://highwire.stanford.edu title The Gardner syndrome: significance of ocular features. mimNumber 175100 referenceNumber 109 pubmedID 6493700 source Ophthalmology 91: 916-925, 1984. authors Lewis, R. A., Crowder, W. E., Eierman, L. A., Nussbaum, R. L., Ferrell, R. E. pubmedImages false title Basal cell carcinoma in Gardner's syndrome. mimNumber 175100 referenceNumber 110 pubmedID 4100336 source Acta Derm. Venerol. 51: 67-68, 1971. authors Lewis, R. J., Mitchell, J. C. pubmedImages false title Hepatoblastoma in families with polyposis coli. mimNumber 175100 referenceNumber 111 pubmedID 3033343 source JAMA 257: 2475-2477, 1987. authors Li, F. P., Thurber, W. A., Seddon, J., Holmes, G. E. pubmedImages false title Phenotypic, cytogenetic, and molecular studies of three patients with constitutional deletions of chromosome 5 in the region of the gene for familial adenomatous polyposis. mimNumber 175100 referenceNumber 112 pubmedID 1315124 source Am. J. Hum. Genet. 50: 988-997, 1992. authors Lindgren, V., Bryke, C. R., Ozcelik, T., Yang-Feng, T. L., Francke, U. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198407123110202?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Ornithine decarboxylase as a biologic marker in familial colonic polyposis. mimNumber 175100 referenceNumber 113 publisherAbbreviation ATYPON pubmedID 6738598 source New Eng. J. Med. 311: 80-83, 1984. authors Luk, G. D., Baylin, S. B. pubmedImages false publisherUrl http://www.atypon.com/ title Desmoid tumors: genotype-phenotype differences in familial adenomatous polyposis: a nosological dilemma. (Editorial) mimNumber 175100 referenceNumber 114 pubmedID 8940262 source Am. J. Hum. Genet. 59: 1184-1185, 1996. authors Lynch, H. T. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMra012242?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Hereditary colorectal cancer. mimNumber 175100 referenceNumber 115 publisherAbbreviation ATYPON pubmedID 12621137 source New Eng. J. Med. 348: 919-932, 2003. authors Lynch, H. T., de la Chapelle, A. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62769-4 publisherName Elsevier Science title Classification of familial adenomatous polyposis: a diagnostic nightmare. (Editorial) mimNumber 175100 referenceNumber 116 publisherAbbreviation ES pubmedID 9585618 source Am. J. Hum. Genet. 62: 1288-1289, 1998. authors Lynch, H. T., Smyrk, T. C. pubmedImages false publisherUrl http://www.elsevier.com/ title Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis? mimNumber 175100 referenceNumber 117 pubmedID 1314729 source Dis. Colon Rectum 35: 411-421, 1992. authors Lynch, H. T., Smyrk, T. C., Watson, P., Lanspa, S. J., Lynch, P. M., Jenkins, J. X., Rouse, J., Cavalieri, J., Howard, L., Lynch, J. pubmedImages false title A genetic study of Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium. mimNumber 175100 referenceNumber 118 pubmedID 3422541 source Am. J. Hum. Genet. 42: 290-296, 1988. authors Lyons, L. A., Lewis, R. A., Strong, L. C., Zuckerbrod, S., Ferrell, R. E. pubmedImages false title Gardner's syndrome and periampullary malignancy. mimNumber 175100 referenceNumber 119 pubmedID 6018692 source Am. J. Surg. 113: 425-430, 1967. authors MacDonald, J. M., Davis, W. C., Crago, H. R., Berk, A. D. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8105087 publisherName HighWire Press title Evaluation of molecular genetic diagnosis in the management of familial adenomatous polyposis coli: a population based study. mimNumber 175100 referenceNumber 120 publisherAbbreviation HighWire pubmedID 8105087 source J. Med. Genet. 30: 675-678, 1993. authors Maher, E. R., Barton, D. E., Slatter, R., Koch, D. J., Jones, M. H., Nagase, H., Payne, S. J., Charles, S. J., Moore, A. T., Nakamura, Y., Ferguson-Smith, M. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199509073331011?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Aspirin as prophylaxis against colorectal cancer. mimNumber 175100 referenceNumber 121 publisherAbbreviation ATYPON pubmedID 7637730 source New. Eng. J. Med. 333: 656-658, 1995. authors Marcus, A. J. pubmedImages false publisherUrl http://www.atypon.com/ title Gardner's syndrome with adrenal carcinoma. mimNumber 175100 referenceNumber 122 pubmedID 6056613 source Australas. Ann. Med. 16: 242-244, 1967. authors Marshall, W. H., Martin, F. I. R., MacKay, I. R. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12810952 publisherName HighWire Press title Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. mimNumber 175100 referenceNumber 123 publisherAbbreviation HighWire pubmedID 12810952 source Proc. Nat. Acad. Sci. 100: 7859-7864, 2003. authors Martinez, M. E., O'Brien, T. G., Fultz, K. E., Babbar, N., Yerushalmi, H., Qu, N., Guo, Y., Boorman, D., Einspahr, J., Alberts, D. S., Gerner, E. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=11839722 publisherName HighWire Press title Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation. mimNumber 175100 referenceNumber 124 publisherAbbreviation HighWire pubmedID 11839722 source Gut 50: 402-404, 2002. authors Matsumoto, T., Iida, M., Mizuno, M., Nakamura, S., Hizawa, K., Yao, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199401203300307?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Screening for colorectal cancer by nurse endoscopists. mimNumber 175100 referenceNumber 125 publisherAbbreviation ATYPON pubmedID 8264742 source New Eng. J. Med. 330: 183-187, 1994. authors Maule, W. 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W. pubmedImages false articleUrl http://dx.doi.org/10.1054/bjoc.1999.1007 publisherName Nature Publishing Group title Desmoids in familial adenomatous polyposis are monoclonal proliferations. mimNumber 175100 referenceNumber 128 publisherAbbreviation NPG pubmedID 10732754 source Brit. J. Cancer 82: 827-832, 2000. authors Middleton, S. B., Frayling, I. M., Phillips, R. K. S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1316610 publisherName HighWire Press title Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. mimNumber 175100 referenceNumber 129 publisherAbbreviation HighWire pubmedID 1316610 source Proc. Nat. Acad. Sci. 89: 4452-4456, 1992. authors Miyoshi, Y., Ando, H., Nagase, H., Nishisho, I., Horii, A., Miki, Y., Mori, T., Utsunomiya, J., Baba, S., Petersen, G., Hamilton, S. R., Kinzler, K. 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A. pubmedImages false title Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5. mimNumber 175100 referenceNumber 132 pubmedID 2903664 source Am. J. Hum. Genet. 43: 638-644, 1988. authors Nakamura, Y., Lathrop, M., Leppert, M., Dobbs, M., Wasmuth, J., Wolff, E., Carlson, M., Fujimoto, E., Krapcho, K., Sears, T., Woodward, S., Hughes, J., Burt, R., Gardner, E., Lalouel, J.-M., White, R. pubmedImages false title Adrenal adenomas in a patient with Gardner's syndrome. mimNumber 175100 referenceNumber 133 pubmedID 7296952 source Clin. Genet. 20: 67-73, 1981. authors Naylor, E. W., Gardner, E. J. pubmedImages false title Penetrance and expressivity of the gene responsible for the Gardner syndrome. mimNumber 175100 referenceNumber 134 pubmedID 880737 source Clin. Genet. 11: 381-393, 1977. authors Naylor, E. W., Gardner, E. J. pubmedImages false title Gardner's syndrome: recent developments in research and management. mimNumber 175100 referenceNumber 135 pubmedID 7004810 source Digest. Dis. Sci. 25: 945-959, 1980. authors Naylor, E. W., Lebenthal, E. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1651563 publisherName HighWire Press title Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. mimNumber 175100 referenceNumber 136 publisherAbbreviation HighWire pubmedID 1651563 source Science 253: 665-669, 1991. authors Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., Hedge, P., Markham, A., Krush, A. J., Petersen, G., Hamilton, S. R., Nilbert, M. C., Levy, D. B., Bryan, T. M., Preisinger, A. C., Smith, K. J., Su, L.-K., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8638166 publisherName HighWire Press title Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. mimNumber 175100 referenceNumber 137 publisherAbbreviation HighWire pubmedID 8638166 source Science 272: 1187-1190, 1996. authors Novelli, M. R., Williamson, J. A., Tomlinson, I. P. M., Elia, G., Hodgson, S. V., Talbot, I. C., Bodmer, W. F., Wright, N. A. pubmedImages false publisherUrl http://highwire.stanford.edu title The risk of upper gastrointestinal cancer in familial adenomatous polyposis. mimNumber 175100 referenceNumber 138 pubmedID 1316858 source Gastroenterology 102: 1980-1982, 1992. authors Offerhaus, G. J. A., Giardiello, F. M., Krush, A. J., Booker, S. V., Tersmette, A. C., Kelley, N. C., Hamilton, S. R. pubmedImages false title Molecular nature of chromosome 5q loss in colorectal tumors and desmoids from patients with familial adenomatous polyposis. mimNumber 175100 referenceNumber 139 pubmedID 2172153 source Hum. Genet. 85: 595-599, 1990. authors Okamoto, M., Sato, C., Kohno, Y., Mori, T., Iwama, T., Tonomura, A., Miki, Y., Utsunomiya, J., Nakamura, Y., White, R., Miyaki, M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)81988-1 publisherName Elsevier Science title Suppression of intestinal polyposis in Apc(delta-716) knockout mice by inhibition of cyclooxygenase 2 (COX-2). mimNumber 175100 referenceNumber 140 publisherAbbreviation ES pubmedID 8945508 source Cell 87: 803-809, 1996. authors Oshima, M., Dinchuk, J. E., Kargman, S. L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J. M., Evans, J. F., Taketo, M. M. pubmedImages false publisherUrl http://www.elsevier.com/ title IgG heavy-chain (Gm) allotypes in familial polyposis coli. mimNumber 175100 referenceNumber 141 pubmedID 3092642 source Am. J. Hum. Genet. 39: 133-136, 1986. authors Pandey, J. P., Ebbesen, P., Bulow, S., Svendsen, L. B., Fudenberg, H. H. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng0995-99 publisherName Nature Publishing Group title Monoallelic mutation analysis (MAMA) for identifying germline mutations. mimNumber 175100 referenceNumber 142 publisherAbbreviation NPG pubmedID 7550326 source Nature Genet. 11: 99-102, 1995. authors Papadopoulos, N., Leach, F. S., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jco.org/cgi/pmidlookup?view=long&pmid=9215849 publisherName HighWire Press title Brain tumor-polyposis syndrome: two genetic diseases? mimNumber 175100 referenceNumber 143 publisherAbbreviation HighWire pubmedID 9215849 source J. Clin. Oncol. 15: 2744-2758, 1997. authors Paraf, F., Jothy, S., Van Meir, E. G. pubmedImages false publisherUrl http://highwire.stanford.edu title Gardner syndrome and periampullary malignancy. mimNumber 175100 referenceNumber 144 pubmedID 6999900 source Am. J. Med. Genet. 6: 205-219, 1980. authors Pauli, R. M., Pauli, M. E., Hall, J. G. pubmedImages false title Hereditary polyposis coli. I. The diagnostic value of colonoscopy, barium enema, and fecal occult blood. mimNumber 175100 referenceNumber 145 pubmedID 922704 source Cancer 40: 2632-2639, 1977. authors Pavlides, G. P., Milligan, F. D., Clark, D. N., Cohen, S. B., Wennstrom, C. J., Burbige, E. J., Krush, A. J., Murphy, E. A. pubmedImages false title Presymptomatic direct detection of adenomatous polyposis coli (APC) gene mutations in familial adenomatous polyposis. mimNumber 175100 referenceNumber 146 pubmedID 8388848 source Hum. Genet. 91: 307-311, 1993. authors Petersen, G. M., Francomano, C., Kinzler, K., Nakamura, Y. pubmedImages false source Am. J. Hum. Genet. 45 (suppl.): A125 only, 1989. mimNumber 175100 authors Petersen, G. M., Shohat, T., Brown, J., Nakamura, Y. title Genetic counseling for familial adenomatous polyposis (FAP) with chromosome 5q linkage information. (Abstract) referenceNumber 147 title Polyposis and carcinoma of the small bowel and familial colonic polyposis. mimNumber 175100 referenceNumber 148 pubmedID 7273988 source Dis. Colon Rectum 24: 478-481, 1981. authors Phillips, L. G., Jr. pubmedImages false source Birth Defects Orig. Art. Ser. VII(2): 52-62, 1972. mimNumber 175100 authors Pierce, E. R. title Pleiotropism and heterogeneity in hereditary intestinal polyposis. referenceNumber 149 source Clin. Genet. 1: 65-80, 1970. mimNumber 175100 authors Pierce, E. R., Weisbord, T., McKusick, V. A. title Gardner's syndrome: formal genetics and statistical analysis of a large Canadian kindred. referenceNumber 150 articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201157 publisherName Nature Publishing Group title Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred. mimNumber 175100 referenceNumber 151 publisherAbbreviation NPG pubmedID 14735163 source Europ. J. Hum. Genet. 12: 365-371, 2004. authors Plasilova, M., Russell, A. M., Wanner, A., Wolf, A., Dobbie, Z., Muller, H. J., Heinimann, K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM199312303292702?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Molecular diagnosis of familial adenomatous polyposis. mimNumber 175100 referenceNumber 152 publisherAbbreviation ATYPON pubmedID 8247073 source New Eng. J. Med. 329: 1982-1987, 1993. authors Powell, S. M., Petersen, G. M., Krush, A. J., Booker, S., Jen, J., Giardiello, F. M., Hamilton, S. R., Vogelstein, B., Kinzler, K. W. pubmedImages false publisherUrl http://www.atypon.com/ title Inherited susceptibility to retrovirus-induced transformation of Gardner syndrome cells. mimNumber 175100 referenceNumber 153 pubmedID 6310993 source Am. J. Hum. Genet. 35: 919-931, 1983. authors Rasheed, S., Rhim, J. S., Gardner, E. J. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=3486977 publisherName HighWire Press title Familial polyposis coli: growth characteristics of karyotypically variable cultured fibroblasts, response to epidermal growth factor and the tumour promoter 12-0-tetradecanoyl phorbol-13-acetate. mimNumber 175100 referenceNumber 154 publisherAbbreviation HighWire pubmedID 3486977 source J. Med. Genet. 23: 131-144, 1986. authors Rider, S. H., Mazzullo, H. A., Davis, M. B., Delhanty, J. D. 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G. pubmedImages false title Polyposis coli associated with multiple tumours in other parts of the body (Gardner's syndrome). mimNumber 175100 referenceNumber 158 pubmedID 14168852 source Proc. Roy. Soc. Med. 57: 402-403, 1964. authors Savage, P. T. pubmedImages false title Association of endocrine neoplasia with multiple polyposis of the colon. mimNumber 175100 referenceNumber 159 pubmedID 6129922 source Cancer 51: 1171-1175, 1983. authors Schneider, N. R., Cubilla, A. L., Chaganti, R. S. K. pubmedImages false articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=8707116 publisherName HighWire Press title Sulindac increases the expression of APC mRNA in malignant colonic epithelial cells: an in vitro study. mimNumber 175100 referenceNumber 160 publisherAbbreviation HighWire pubmedID 8707116 source Gut 38: 707-713, 1996. authors Schnitzler, M., Dwight, T., Robinson, B. G. pubmedImages false publisherUrl http://highwire.stanford.edu title Duodenal cancer and Gardner syndrome. mimNumber 175100 referenceNumber 161 pubmedID 4739325 source JAMA 223: 1229-1232, 1973. authors Schnur, P. L., David, E., Brown, P. W., Jr., Beahrs, O. H., Remine, W. H., Harrison, E. G., Jr. pubmedImages false title Adenomatous polyp of the common bile duct in familial polyposis coli. mimNumber 175100 referenceNumber 162 pubmedID 4044238 source Isr. J. Med. Sci. 21: 701-702, 1985. authors Shemesh, E. pubmedImages false title Adenocarcinoma arising from congenital hypertrophy of retinal pigment epithelium. mimNumber 175100 referenceNumber 163 pubmedID 11296028 source Arch. Ophthal. 119: 597-602, 2001. authors Shields, J. A., Shields, C. L., Eagle, R. C., Jr., Singh, A. D. pubmedImages false title Acquired tumors arising from congenital hypertrophy of the retinal pigment epithelium. mimNumber 175100 referenceNumber 164 pubmedID 10815155 source Arch. Ophthal. 118: 637-641, 2000. authors Shields, J. A., Shields, C. L., Singh, A. D. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11226292 publisherName HighWire Press title Top-down morphogenes is of colorectal tumors. mimNumber 175100 referenceNumber 165 publisherAbbreviation HighWire pubmedID 11226292 source Proc. Nat. Acad. Sci. 98: 2640-2645, 2001. authors Shih, I.-M., Wang, T.-L., Traverso, G., Romans, K., Hamilton, S. R., Ben-Sasson, S., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://highwire.stanford.edu title Familial adenomatous polyposis following liver transplantation for a virilizing hepatoblastoma. mimNumber 175100 referenceNumber 166 pubmedID 1328581 source J. Pediat. Gastroent. Nutr. 15: 198-201, 1992. authors Shneider, B. L., Haque, S., van Hoff, J., Touloukian, R. J., West, A. B. pubmedImages false title Lymphoid polyposis associated with familial polyposis and Gardner's syndrome. mimNumber 175100 referenceNumber 167 pubmedID 4853059 source Ann. Surg. 180: 319-322, 1974. authors Shull, L. N., Jr., Fitts, C. T. pubmedImages false title Mesenteric fibromatosis in familial polyposis: a variant of Gardner's syndrome. mimNumber 175100 referenceNumber 168 pubmedID 14136536 source Cancer 17: 526-534, 1964. authors Simpson, R. D., Harrison, E. G., Jr., Mayo, C. W. pubmedImages false title Upper gastrointestinal endoscopy in polyposis syndromes: familial polyposis coli and Gardner's syndrome. mimNumber 175100 referenceNumber 169 pubmedID 6714590 source Gastrointest. Endosc. 30: 102-104, 1984. authors Sivak, M. V., Jagelman, D. G. pubmedImages false title Familial multiple polyposis: research tool for investigating the etiology of carcinoma of the colon? mimNumber 175100 referenceNumber 170 pubmedID 5639668 source Dis. Colon Rectum 11: 17-31, 1968. authors Smith, W. G. pubmedImages false title Multiple polyposis, Gardner's syndrome and desmoid tumors. mimNumber 175100 referenceNumber 171 pubmedID 13574046 source Dis. Colon Rectum 1: 323-332, 1958. authors Smith, W. G. pubmedImages false articleUrl http://dx.doi.org/10.1038/328616a0 publisherName Nature Publishing Group title Chromosome 5 allele loss in human colorectal carcinomas. mimNumber 175100 referenceNumber 172 publisherAbbreviation NPG pubmedID 2886919 source Nature 328: 616-619, 1987. authors Solomon, E., Voss, R., Hall, V., Bodmer, W. F., Jass, J. R., Jeffreys, A. J., Lucibello, F. C., Patel, I., Rider, S. H. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62770-0 publisherName Elsevier Science title Genotype-phenotype correlations in attenuated adenomatous polyposis coli. mimNumber 175100 referenceNumber 173 publisherAbbreviation ES pubmedID 9585611 source Am. J. Hum. Genet. 62: 1290-1301, 1998. authors Soravia, C., Berk, T., Madlensky, L., Mitri, A., Cheng, H., Gallinger, S., Cohen, Z., Bapat, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM200006293422603?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. mimNumber 175100 referenceNumber 174 publisherAbbreviation ATYPON pubmedID 10874062 source New Eng. J. Med. 342: 1946-1952, 2000. authors Steinbach, G., Lynch, P. M., Phillips, R. K. S., Wallace, M. H., Hawk, E., Gordon, G. B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., Su, L.-K., Levin, B. pubmedImages false publisherUrl http://www.atypon.com/ title Exclusion of the APC gene as the cause of a variant form of familial adenomatous polyposis (FAP). mimNumber 175100 referenceNumber 175 pubmedID 8213830 source Am. J. Hum. Genet. 53: 1031-1037, 1993. authors Stella, A., Resta, N., Gentile, M., Susca, F., Mareni, C., Montera, M. P., Guanti, G. pubmedImages false title Gardner's syndrome associated with periampullary carcinoma, duodenal and gastric adenomatosis: report of a case. mimNumber 175100 referenceNumber 176 pubmedID 7172944 source Dis. Colon Rectum 25: 766-771, 1982. authors Sugihara, K., Muto, T., Kamiya, J., Konishi, F., Sawada, T., Morioka, Y. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7666398 publisherName HighWire Press title The dental phenotype in familial adenomatous polyposis: diagnostic application of a weighted scoring system for changes on dental panoramic radiographs. mimNumber 175100 referenceNumber 177 publisherAbbreviation HighWire pubmedID 7666398 source J. Med. Genet. 32: 458-464, 1995. authors Thakker, N., Davies, R., Horner, K., Armstrong, J., Clancy, T., Guy, S., Harris, R., Sloan, P., Evans, G. pubmedImages false publisherUrl http://highwire.stanford.edu title Papillary carcinoma of the thyroid and familial polyposis coli. mimNumber 175100 referenceNumber 178 pubmedID 6872788 source Dis. Colon Rectum 26: 583-585, 1983. authors Thompson, J. S., Harned, R. K., Anderson, J. C., Hodgson, P. E. pubmedImages false articleUrl http://link.springer-ny.com/link/service/journals/00268/bibs/4028009/40280886.html publisherName Springer title Cribriform-morular variant of papillary thyroid carcinoma: clue to early detection of familial adenomatous polyposis-associated colon cancer. mimNumber 175100 referenceNumber 179 publisherAbbreviation Springer pubmedID 15593462 source World J. Surg. 28: 886-889, 2004. authors Tomoda, C., Miyauchi, A., Uruno, T., Takamura, Y., Ito, Y., Miya, A., Kobayashi, K., Matsuzuka, F., Kuma, S., Kuma, K., Kakudo, K. pubmedImages false publisherUrl http://www.springeronline.com/ title Non-allelic heterogeneity of familial adenomatous polyposis. mimNumber 175100 referenceNumber 180 pubmedID 8256823 source Am. J. Med. Genet. 47: 563-567, 1993. authors Tops, C. M. J., van der Klift, H. M., van der Luijt, R. B., Griffioen, G., Taal, B. G., Vasen, H. F. A., Khan, P. M. pubmedImages false title Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis. mimNumber 175100 referenceNumber 181 pubmedID 1322639 source Am. J. Med. Genet. 43: 888-893, 1992. authors Tops, C. M. J., Vasen, H. F. A., van Berge Henegouwen, G., Simoons, P. P., van de Klift, H. M., van Leeuwen, I. S. J., Breukel, C., Fodde, R., den Hartog Jager, F. C. A., Nagengast, F. M., Griffioen, G., Meera Khan, P. pubmedImages false title Presymptomatic diagnosis of familial adenomatous polyposis by bridging DNA markers. mimNumber 175100 referenceNumber 182 pubmedID 2574305 source Lancet 334: 1361-1363, 1989. Note: Originally Volume 2. authors Tops, C. M. J., Wijnen, J. T., Griffioen, G., van Leeuwen, I. S. J., Vasen, H. F. A., den Hartog Jager, F. C. A., Breukel, C., Nagengast, F. M., van der Klift, H. M., Lamers, C. B. H. W., Meera Khan, P. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198703123161104?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. mimNumber 175100 referenceNumber 183 publisherAbbreviation ATYPON pubmedID 3821797 source New Eng. J. Med. 316: 661-667, 1987. authors Traboulsi, E. I., Krush, A. J., Gardner, E. J., Booker, S. V., Offerhaus, G. J. A., Yardley, J. H., Hamilton, S. R., Luk, G. D., Giardiello, F. M., Welsh, S. B., Hughes, J. P., Maumenee, I. H. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa012294?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Detection of APC mutations in fecal DNA from patients with colorectal tumors. mimNumber 175100 referenceNumber 184 publisherAbbreviation ATYPON pubmedID 11821507 source New Eng. J. Med. 346: 311-320, 2002. authors Traverso, G., Shuber, A., Levin, B., Johnson, C., Olsson, L., Schoetz, D. J., Jr., Hamilton, S. R., Boynton, K., Kinzler, K. W., Vogelstein, B. pubmedImages false publisherUrl http://www.atypon.com/ title The occult osteomatous changes in the mandible in patients with familial polyposis coli. mimNumber 175100 referenceNumber 185 pubmedID 1111674 source Brit. J. Surg. 62: 45-51, 1975. authors Utsunomiya, J., Nakamura, T. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(84)71119-0 publisherName Elsevier Science title Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test. mimNumber 175100 referenceNumber 186 publisherAbbreviation ES pubmedID 8020934 source Genomics 20: 1-4, 1994. authors van der Luijt, R., Meera Khan, P., Vasen, H., van Leeuwen, C., Tops, C., Roest, P., den Dunnen, J., Fodde, R. pubmedImages false publisherUrl http://www.elsevier.com/ title Molecular, cytogenetic, and phenotypic studies of a constitutional reciprocal translocation t(5;10)(q22;q25) responsible for familial adenomatous polyposis in a Dutch pedigree. mimNumber 175100 referenceNumber 187 pubmedID 7669739 source Genes Chromosomes Cancer 13: 192-202, 1995. authors van der Luijt, R. B., Tops, C. M. J., Khan, P. M., van der Klift, H. M., Breukel, C., van Leeuwen-Cornelisse, I. S. J., Dauwerse, H. G., Beverstock, G. C., van Noort, E., Snel, P., Slors, F. J. M., Vasen, H. F. A., Fodde, R. pubmedImages false title Polypoid lymphoid hyperplasia of the terminal ileum in patients with familial polyposis coli and with Gardner's syndrome. mimNumber 175100 referenceNumber 188 pubmedID 5472667 source Am. J. Roentgen. 110: 340-342, 1970. authors Vanhoutte, J. J. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1097-0215(19980105)75:1<162::AID-IJC26>3.0.CO;2-H publisherName John Wiley & Sons, Inc. title 'Turcot's syndrome': phenotype of brain tumors, survival and mode of inheritance. (Letter) mimNumber 175100 referenceNumber 189 publisherAbbreviation Wiley pubmedID 9426707 source Int. J. Cancer 75: 162-164, 1998. authors Van Meir, E. G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2557613 publisherName HighWire Press title CpG island clones from a deletion encompassing the gene for adenomatous polyposis coli. mimNumber 175100 referenceNumber 190 publisherAbbreviation HighWire pubmedID 2557613 source Proc. Nat. Acad. Sci. 86: 10118-10122, 1989. authors Varesco, L., Thomas, H. J. W., Cottrell, S., Murday, V., Fennell, S. J., Williams, S., Searle, S., Sheer, D., Bodmer, W. F., Frischauf, A.-M., Solomon, E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=13780515 publisherName HighWire Press title Clinical and genetic problems in familial intestinal polyposis. mimNumber 175100 referenceNumber 191 publisherAbbreviation HighWire pubmedID 13780515 source Gut 1: 285-290, 1960. authors Veale, A. M. pubmedImages false publisherUrl http://highwire.stanford.edu title Multiple lymphoid polyposis and familial polyposis of the colon: a genetic relationship. mimNumber 175100 referenceNumber 192 pubmedID 699723 source Dis. Colon Rectum 21: 336-341, 1978. authors Venkitachalam, P. S., Hirsch, E., Elguezabal, A., Littman, L. pubmedImages false title Sulindac for polyposis of the colon. mimNumber 175100 referenceNumber 193 pubmedID 6887943 source J. Surg. Oncol. 24: 83-87, 1983. authors Waddell, W. R., Loughry, R. W. pubmedImages false title Biliary neoplasia in Gardner's syndrome. mimNumber 175100 referenceNumber 194 pubmedID 3800608 source Arch. Path. Lab. Med. 111: 76-77, 1987. authors Walsh, N., Qizilbash, A., Banerjee, R., Waugh, G. A. pubmedImages false title Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. mimNumber 175100 referenceNumber 195 pubmedID 26633 source Hum. Path. 9: 269-283, 1978. authors Watanabe, H., Enjoji, M., Yao, T., Ohsato, K. pubmedImages false articleUrl http://archsurg.ama-assn.org/cgi/pmidlookup?view=long&pmid=5808270 publisherName HighWire Press title Familial polyposis of the entire gastrointestinal tract. mimNumber 175100 referenceNumber 196 publisherAbbreviation HighWire pubmedID 5808270 source Arch. Surg. 99: 427-434, 1969. authors Yanemoto, R. H., Slayback, J. B., Byron, R. L., Jr., Rosen, R. B. pubmedImages false publisherUrl http://highwire.stanford.edu seeAlso Armstrong et al. (1997); Benecke (1931); Berk et al. (1981); Botstein et al. (1980); Chang et al. (1968); Danes (1975); Danes (1976); Davies et al. (1995); Dhaliwal et al. (1990); Duhamel et al. (1960); Eccles et al. (1997); Endo and Kasukawa (1987); Giardiello et al. (1997); Haggitt and Booth (1970); Hyson and Burrell (1976); Ingram and Oldfield (1937); Kaplan et al. (1982); Kartheuser et al. (1999); Leffall et al. (1977); Leppard and Bussey (1975); Lewis and Mitchell (1971); Lindgren et al. (1992); Lynch and de la Chapelle (2003); MacDonald et al. (1967); McKusick (1962); Murphy et al. (1980); Naylor and Lebenthal (1980); Pavlides et al. (1977); Phillips (1981); Pierce (1972); Rider et al. (1986); Sanchez et al. (1979); Schneider et al. (1983); Shemesh (1985); Sivak and Jagelman (1984); Thompson et al. (1983); Tops et al. (1992); Vanhoutte (1970); Veale (1960); Watanabe et al. (1978); Yanemoto et al. (1969)

entryList

entry status live allelicVariantExists true epochCreated 894438000 geneMap geneSymbols OLR1, LOX1 sequenceID 8883 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 602601 phenotypeInheritance None phenotype {Myocardial infarction, susceptibility to} phenotypeMimNumber 608446 chromosomeLocationStart 10310898 chromosomeSort 128 chromosomeSymbol 12 mimNumber 602601 geneInheritance None confidence C mappingMethod A, REn geneName Low density lipoprotein, oxidized, receptor 1 mouseMgiID MGI:1261434 mouseGeneSymbol Olr1 computedCytoLocation 12p13.2 cytoLocation 12p13-p12 transcript uc001qxo.1 chromosomeLocationEnd 10324789 chromosome 12 contributors Paul J. Converse - updated : 1/6/2006 Jane Kelly - updated : 3/1/2005 Marla J. F. O'Neill - updated : 10/14/2004 Cassandra L. Kniffin - reorganized : 8/26/2004 Cassandra L. Kniffin - updated : 8/23/2004 Victor A. McKusick - updated : 4/29/2004 Victor A. McKusick - updated : 11/13/2002 Carol A. Bocchini - updated : 2/24/1999 clinicalSynopsisExists false mimNumber 602601 allelicVariantList allelicVariant status removed number 1 name REMOVED FROM DATABASE status live name MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO dbSnps rs11053646 text {12:Tatsuguchi et al. (2003)} identified a single nucleotide polymorphism in the LOX1 gene, a 501G-C transversion, resulting in a lys167-to-asn (K167N) substitution. In 102 patients with a history of myocardial infarction ({608446}), the authors found a significantly higher frequency (38.2%) of the 501G-C polymorphism compared to 102 controls (17.6%). The odds ratio for the risk of MI associated with the 501G-C change was 2.89. mutations LOX1, LYS167ASN number 2 clinvarAccessions RCV000007409;;1 status live name MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO text {8:Mango et al. (2003)} identified a polymorphism in the 3-prime UTR of the LOX1 gene, a C-to-T change 188 nucleotides from the stop codon (3-prime UTR +188C-T), that was significantly associated with myocardial infarction ({608446}) in a group of 150 patients. Genotypes with the T allele were found in 91.3% of patients compared to 73.8% of controls, yielding an odds ratio of 3.74. In a study of 589 white and 122 black women who underwent angiography for suspected ischemia, {3:Chen et al. (2003)} found that the frequency of the 3-prime UTR T allele was significantly higher in whites than in blacks (p less than 0.0001). Among white women, the frequency of the T allele was 67.9%, 75.0%, and 79.2% in individuals with less than 20%, 20 to 49%, and greater than 49% stenosis, respectively (chi square trend = 6.23, p = 0.013). The T-allele carriers had significantly higher IgG anti-oxLDL levels than those with the CC genotype (p = 0.032); and electrophoretic mobility shift assay data indicated that the 3-prime UTR binds regulatory proteins and that the C allele has a higher affinity for binding than the T allele. mutations LOX1, +188C-T, 3-PRIME UTR number 3 clinvarAccessions RCV000007410;;1 prefix * titles alternativeTitles LECTIN-LIKE OXIDIZED-LDL RECEPTOR 1; LOX1;; OXIDIZED LOW DENSITY LIPOPROTEIN RECEPTOR 1 preferredTitle LOW DENSITY LIPOPROTEIN, OXIDIZED, RECEPTOR 1; OLR1 textSectionList textSection textSectionTitle Description textSectionContent The OLR1 gene encodes a cell-surface endocytosis receptor for oxidized low density lipoprotein (OxLDL). LDL is oxidized in vascular endothelial cells to a highly injurious product that results in endothelial cell injury, which is implicated in the development of atherosclerosis. Vascular endothelial cells also internalize and degrade OxLDL though the OLR1 receptor ({9:Mehta and Li, 1998}). textSectionName description textSectionTitle Cloning textSectionContent {11:Sawamura et al. (1997)} isolated a bovine aortic endothelial cell cDNA encoding a 270-amino acid OxLDL receptor protein, which they termed LOX1. {11:Sawamura et al. (1997)} cloned a human LOX1 cDNA from a lung cDNA library. The deduced 273-amino acid protein shares 72% sequence identity with the bovine protein and has a structure similar to that of several lectin-like killer cell receptors such as CD94 (KLRD1; {602894}) and NKR-P1 (KLRB1; {602890}). Northern blot analysis detected a 2.8-kb LOX1 mRNA in various tissues, with highest expression in placenta. Immunofluorescence studies showed that bovine LOX1 is expressed on the cell surface. Cells stably expressing human LOX1 showed uptake of labeled OxLDL. {13:Yamanaka et al. (1998)} determined that LOX1 is expressed in vascular-rich organs but not in lymphocytes. textSectionName cloning textSectionTitle Gene Structure textSectionContent {13:Yamanaka et al. (1998)} determined that the LOX1 gene spans approximately 15 kb and contains 6 exons. {1:Aoyama et al. (1999)} determined the detailed structure of the LOX1 gene. The first 3 exons corresponded to the different functional domains of the protein, cytoplasmic, transmembrane, and neck domains, and the last 3 exons encoded the carbohydrate-recognition domain common to other C-type lectin genes. textSectionName geneStructure textSectionTitle Mapping textSectionContent By fluorescence in situ hybridization, {13:Yamanaka et al. (1998)} mapped the LOX1 gene to 12p13-p12. They noted that several genes encoding natural killer cell receptors are clustered in the same region. By fluorescence in situ hybridization, {1:Aoyama et al. (1999)} refined the LOX1 gene location to 12p13.2-p12.3. textSectionName mapping textSectionTitle Gene Function textSectionContent {9:Mehta and Li (1998)} detected LOX1 mRNA in cultures of human coronary artery endothelial cells (HCAEC), and binding assays indicated a significant number of high-affinity binding sites on the cells. Incubation of the cells with LDL had no effect on LOX1 expression, but incubation with OxLDL resulted in a dose-dependent increase in LOX1 mRNA and protein expression; however, very high concentrations of OxLDL caused a decrease in OxLDL expression, perhaps indicating toxic effects on endothelial cells. Scavenger receptors on the surface of macrophages play a role in the uptake of modified lipoproteins such as OxLDL, resulting in foam cell formation, a pathogenic change found in atherosclerosis. By RT-PCR, immunohistochemistry, flow cytometry, and Western blot analysis, {14:Yoshida et al. (1998)} demonstrated that LOX1 is expressed on the plasma membrane of differentiated macrophages, but not on monocytes. Western blot analysis identified a 40-kD protein which specifically recognized moderately oxidized LDL, but not fully oxidized LDL or native LDL. The findings indicated that the LOX1 protein acts as a macrophage scavenger receptor (see e.g., MSR1, {153622}). In rat cultured vascular endothelial cells, {10:Nagase et al. (1998)} found that LOX1 gene expression was upregulated 9-fold by shear stress, 21-fold by lipopolysaccharide, and 4-fold by tumor necrosis factor-alpha (TNFA; {191160}). LOX1 was also expressed in macrophages, but not in vascular smooth muscle cells. The findings suggested a role for LOX1 in the pathophysiology of atherosclerotic cardiovascular disease. Heat shock proteins (HSPs) are molecular chaperones that control protein folding and prevent aggregation of proteins. They complex with peptides and bind to dendritic cells (DCs) and macrophages before being internalized in a receptor-dependent manner. HSPs then colocalize with MHC class I molecules to initiate protective and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Using flow cytometric and Western blot analyses with binding inhibition assays, {4:Delneste et al. (2002)} found that HSP70 ({140550}) bound LOX1, but not other scavenger receptors tested, on both DCs and macrophages to gain access to the MHC class I pathway to initiate CTL responses. {5:Honjo et al. (2004)} examined choroidal neovascular membranes from patients with exudative age-related macular degeneration (ARMD; see {153800}) for expression of LOX1. LOX1 expression was detected in all choroidal neovascular membranes, regardless of structure, whereas there was no evidence of LOX1 within the posterior segments of normal eyes. {5:Honjo et al. (2004)} concluded that their findings suggested that LOX1 plays an active role in the pathogenesis of choroidal neovascularization, especially in ARMD. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Alzheimer Disease Because OLR1 is abundantly expressed in brain and maps close to the A2M gene ({103950}), which had been implicated in a form of Alzheimer disease (AD5; {602096}) mapping to chromosome 12p, {7:Luedecking-Zimmer et al. (2002)} studied OLR1 as a candidate gene for AD5. In more than 800 late-onset Alzheimer disease cases and more than 700 controls, they studied intragenic polymorphisms that showed significant association with Alzheimer disease after stratification by APOE*4. {7:Luedecking-Zimmer et al. (2002)} concluded that genetic variation in the OLR1 gene may modify the risk of Alzheimer disease in an APOE*4-dependent fashion. {6:Lambert et al. (2003)} presented evidence that genetic variation in the OLR1 gene might modify the risk of Alzheimer disease. They described an association of a 3-prime UTR +1073C-T polymorphism of OLR1 with AD in French sporadic and American familial cases. The age- and sex-adjusted odds ratio between the CC/CT genotypes versus the TT genotypes was 1.56 in the French sample and 1.92 in the American sample. In studies of OLR1 expression in lymphocytes from AD cases compared with controls, they found the OLR1 expression significantly lower in AD cases bearing the CC and CT genotypes. Contrary to the findings of {7:Luedecking-Zimmer et al. (2002)} and {6:Lambert et al. (2003)}, {2:Bertram et al. (2004)} found no evidence favoring a genetic involvement of the 3-prime UTR +1073C-T polymorphism of the OLR1 gene in Alzheimer disease. Their study involved a large sample of 437 multiplex AD families. They also observed no linkage disequilibrium between this SNP and polymorphisms in the A2M gene. Cardiovascular Disease In 2 independent studies, {12:Tatsuguchi et al. (2003)} and {8:Mango et al. (2003)} reported an association between polymorphisms in the OLR1 gene ({601602.0002}; {601602.0003}) and myocardial infarction ({608446}). textSectionName molecularGenetics geneMapExists true editHistory alopez : 05/08/2014 alopez : 5/2/2014 carol : 11/2/2011 ckniffin : 4/8/2011 wwang : 11/13/2008 mgross : 3/10/2008 mgross : 3/10/2008 mgross : 1/6/2006 tkritzer : 3/1/2005 terry : 2/18/2005 carol : 10/14/2004 carol : 8/26/2004 carol : 8/26/2004 carol : 8/26/2004 ckniffin : 8/23/2004 tkritzer : 5/3/2004 terry : 4/29/2004 carol : 4/28/2004 terry : 3/30/2004 tkritzer : 2/5/2004 tkritzer : 2/4/2004 tkritzer : 2/2/2004 tkritzer : 11/18/2002 terry : 11/13/2002 terry : 2/25/1999 terry : 2/25/1999 carol : 2/24/1999 psherman : 5/6/1998 dateCreated Wed, 06 May 1998 03:00:00 EDT creationDate Rebekah S. Rasooly : 5/6/1998 epochUpdated 1399532400 dateUpdated Thu, 08 May 2014 03:00:00 EDT referenceList reference articleUrl http://www.biochemj.org/bj/339/0177/bj3390177.htm publisherName Portland Press title Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. mimNumber 602601 referenceNumber 1 publisherAbbreviation Portland pubmedID 10085242 source Biochem. J. 339: 177-184, 1999. authors Aoyama, T., Sawamura, T., Furutani, Y., Matsuoka, R., Yoshida, M. C., Fujiwara, H., Masaki, T. pubmedImages false publisherUrl http://www.portlandpress.co.uk/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15060104 publisherName HighWire Press title No association between a previously reported ORL1 3-prime UTR polymorphism and Alzheimer's disease in a large family sample. mimNumber 602601 referenceNumber 2 publisherAbbreviation HighWire pubmedID 15060104 source J. Med. Genet. 41: 286-288, 2004. authors Bertram, L., Parkinson, M., Mullin, K., Menon, R., Blacker, D., Tanzi, R. E. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12810610 publisherName HighWire Press title Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. mimNumber 602601 referenceNumber 3 publisherAbbreviation HighWire pubmedID 12810610 source Circulation 107: 3146-3151, 2003. authors Chen, Q., Reis, S. E., Kammerer, C., Craig, W. Y., LaPierre, S. E., Zimmer, E. L., McNamara, D. M., Pauly, D. F., Sharaf, B., Holubkov, R., Merz, C. N. B., Sopko, G., Bontempo, F., Kamboh, M. I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1074761302003886 publisherName Elsevier Science title Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. mimNumber 602601 referenceNumber 4 publisherAbbreviation ES pubmedID 12354387 source Immunity 17: 353-362, 2002. authors Delneste, Y., Magistrelli, G., Gauchat, J.-F., Haeuw, J.-F., Aubry, J.-P., Nakamura, K., Kawakami-Honda, N., Goetsch, L., Sawamura, T., Bonnefoy, J.-Y., Jeannin, P. pubmedImages false publisherUrl http://www.elsevier.com/ title Expression of LOX-1, an oxidized low-density lipoprotein receptor, in choroidal neovascularization. mimNumber 602601 referenceNumber 5 pubmedID 15596594 source Arch. Ophthal. 122: 1873-1876, 2004. authors Honjo, M., Sawamura, T., Hinagata, J., Nakamura, K., Sanada, N., Tanihara, H., Honda, Y., Kiryu, J. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=12807963 publisherName HighWire Press title Association of 3-prime-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. mimNumber 602601 referenceNumber 6 publisherAbbreviation HighWire pubmedID 12807963 source J. Med. Genet. 40: 424-430, 2003. authors Lambert, J.-C., Luedecking-Zimmer, E., Merrot, S., Hayes, A., Thaker, U., Desai, P., Houzet, A., Hermant, X., Cottel, D., Pritchard, A., Iwatsubo, T., Pasquier, F., Frigard, B., Conneally, P. M., Chartier-Harlin, M.-C., DeKosky, S. T., Lendon, C., Mann, D., Kamboh, M. I., Amouyel, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1007/s00439-002-0802-7 publisherName Springer title Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. mimNumber 602601 referenceNumber 7 publisherAbbreviation Springer pubmedID 12384789 source Hum. Genet. 111: 443-451, 2002. authors Luedecking-Zimmer, E., DeKosky, S. T., Chen, Q., Barmada, M. M., Kamboh, M. I. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=14684693 publisherName HighWire Press title Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. (Letter) mimNumber 602601 referenceNumber 8 publisherAbbreviation HighWire pubmedID 14684693 source J. Med. Genet. 40: 933-936, 2003. authors Mango, R., Clementi, F., Borgiani, P., Forleo, G. B., Federici, M., Contino, G., Giardina, E., Garza, L., Fahdi, I. E., Lauro, R., Mehta, J. L., Novelli, G., Romeo, F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(98)99004-0 publisherName Elsevier Science title Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells. mimNumber 602601 referenceNumber 9 publisherAbbreviation ES pubmedID 9703956 source Biochem. Biophys. Res. Commun. 248: 511-514, 1998. authors Mehta, J. L., Li, D. Y. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9837956 publisherName HighWire Press title Genomic organization and regulation of expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1) gene. mimNumber 602601 referenceNumber 10 publisherAbbreviation HighWire pubmedID 9837956 source J. Biol. Chem. 273: 33702-33707, 1998. authors Nagase, M., Abe, J., Takahashi, K., Ando, J., Hirose, S., Fujita, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/386073a0 publisherName Nature Publishing Group title An endothelial receptor for oxidized low-density lipoprotein. mimNumber 602601 referenceNumber 11 publisherAbbreviation NPG pubmedID 9052782 source Nature 386: 73-77, 1997. authors Sawamura, T., Kume, N., Aoyama, T., Moriwaki, H., Hoshikawa, H., Aiba, Y., Tanaka, T., Miwa, S., Katsura, Y., Kita, T., Masaki, T. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X03003267 publisherName Elsevier Science title Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction. mimNumber 602601 referenceNumber 12 publisherAbbreviation ES pubmedID 12646194 source Biochem. Biophys. Res. Commun. 303: 247-250, 2003. authors Tatsuguchi, M., Furutani, M., Hinagata, J., Tanaka, T., Furutani, Y., Imamura, S., Kawana, M., Masaki, T., Kasanuki, H., Sawamura, T., Matsuoka, R. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(98)95561-6 publisherName Elsevier Science title The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a novel member of the natural killer gene complex with a unique expression profile. mimNumber 602601 referenceNumber 13 publisherAbbreviation ES pubmedID 9828121 source Genomics 54: 191-199, 1998. authors Yamanaka, S., Zhang, X.-Y., Miura, K., Kim, S., Iwao, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.biochemj.org/bj/334/0009/bj3340009.htm publisherName Portland Press title Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential as a scavenger receptor. mimNumber 602601 referenceNumber 14 publisherAbbreviation Portland pubmedID 9693095 source Biochem. J. 334: 9-13, 1998. authors Yoshida, H., Kondratenko, N., Green, S., Steinberg, D., Quehenberger, O. pubmedImages false publisherUrl http://www.portlandpress.co.uk/ externalLinks mgiIDs MGI:1261434 mgiHumanDisease true ncbiReferenceSequences 290654343,290654341,119392084 refSeqAccessionIDs NG_016743.1 dermAtlas false hprdIDs 04003 swissProtIDs P78380 umlsIDs C1417947 uniGenes Hs.412484 gtr true cmgGene false ensemblIDs ENSG00000173391,ENST00000309539 genbankNucleotideSequences 33468735,19763688,164694166,24472377,123995818,3941299,52092245,194388741,21240476,117576088,148124367,448982815,45751461,83699676,158257679,221046093,30211822,2828355,71516078,4050002,123981011,4049999,18490152,4468343,511799349,194380015,32822728 geneTests false approvedGeneSymbols OLR1 geneIDs 4973 proteinSequences 83699677,448982816,221046094,194380016,3941300,4050004,123995819,194388742,119616563,119616562,18490153,119616565,73621335,119616564,1902984,290654342,123981012,4505501,117576089,290654344,4468344,33468736,158257680,578822879 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 1123570800 geneMap geneSymbols MID1, OGS1, BBBG1, FXY, OSX sequenceID 14400 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 300552 phenotypeInheritance X-linked recessive phenotype Opitz GBBB syndrome, type I phenotypeMimNumber 300000 chromosomeLocationStart 10413349 chromosomeSort 54 chromosomeSymbol X mimNumber 300552 confidence C mappingMethod Fd, Ch geneName Midline-1 comments type II defect on chr.22 geneInheritance None computedCytoLocation Xp22.2 cytoLocation Xp22 transcript uc004cti.4 chromosomeLocationEnd 10851828 chromosome 23 contributors Cassandra L. Kniffin - updated : 12/15/2011 Patricia A. Hartz - updated : 5/27/2008 Victor A. McKusick - updated : 8/17/2005 clinicalSynopsisExists false mimNumber 300552 allelicVariantList allelicVariant status live name OPITZ SYNDROME, X-LINKED text In a family with X-linked Opitz syndrome ({300000}), {13,14:Quaderi et al. (1997, 1997)} identified a 3-bp deletion in the MID1 gene involving a methionine codon. mutations MID1, 3-BP DEL, MET438 number 1 clinvarAccessions RCV000011552;;1 status live name OPITZ SYNDROME, X-LINKED text In a family with X-linked Opitz syndrome ({300000}), {13,14:Quaderi et al. (1997, 1997)} identified a 24-bp duplication in the MID1 gene causing the addition of 8 amino acids to the protein product. mutations MID1, 24-BP DUP number 2 clinvarAccessions RCV000011553;;1 status live name OPITZ SYNDROME, X-LINKED text In a family with X-linked Opitz syndrome ({300000}), {13,14:Quaderi et al. (1997, 1997)} identified a 1-bp insertion in the MID1 gene, resulting in a frameshift and loss of 101 amino acid residues in the protein product. mutations MID1, 1-BP INS number 3 clinvarAccessions RCV000011554;;1 status live name OPITZ SYNDROME, X-LINKED dbSnps rs28934611 text In an isolated patient, {3:Cox et al. (2000)} identified a 1877T-C transition in MID1, resulting in a leu626-to-pro substitution in the carboxyl B30.2 domain of the protein. mutations MID1, LEU626PRO number 4 clinvarAccessions RCV000011555;;1 status live name OPITZ SYNDROME, X-LINKED dbSnps rs104894865 text In an isolated patient, {3:Cox et al. (2000)} identified a 343G-T transversion in MID1, resulting in a glu115-to-ter substitution in the N terminus and truncation of the protein C-terminal to the B-box motifs. Unlike wildtype MID1, cells transiently transfected with this mutant construct in the form of a GFP fusion protein did not colocalize with microtubules. mutations MID1, GLU115TER number 5 clinvarAccessions RCV000011556;;1 status live name OPITZ SYNDROME, X-LINKED text In a patient with Opitz syndrome ({300000}), {17:Winter et al. (2003)} identified a duplication of the first exon of the MID1 gene. The diagnosis of Opitz syndrome was made soon after birth on the basis of a combination of characteristic symptoms. Anal atresia, a rectourethral fistula, and a bifid scrotum were found. In addition, he had a complex heart defect (coarctation of the aorta, patent ductus arteriosus and atrial septal defect secundum type, and abnormal venous return) and a tracheoesophageal cleft. Facial abnormalities comprised hypertelorism, mild downslanting of palpebral fissures, and posteriorly rotated ears. The mother was heterozygous for the duplication and showed mild hypertelorism, a tracheoesophageal cleft, and esophageal stenosis, which was surgically corrected. mutations MID1, EX1 DUP number 6 clinvarAccessions RCV000011557;;1 status live name OPITZ SYNDROME, X-LINKED dbSnps rs104894866 text In a carrier mother and 2 affected sons with Opitz syndrome ({300000}), {16:So et al. (2005)} identified an 884T-C transition in exon 4 of the MID1 gene, predicting a leu295-to-pro substitution (L295P). At the age of 2 years, the older son had evident hypertelorism, cleft lip and palate, hypospadias, a small midline epigastric defect, ureteral dilatation, and, in infancy, he had an enlarged fontanel. The younger son, examined at age 4.5 months, had hypertelorism, hypospadias, and an enlarged fontanel. The mother had hypertelorism, a small midline epigastric defect, and lacked an incisor. mutations MID1, LEU295PRO number 7 clinvarAccessions RCV000011558;;1 status live name OPITZ SYNDROME, X-LINKED text In an Opitz syndrome ({300000}) family with affected members in 3 generations, {16:So et al. (2005)} found a 2-bp deletion in exon 8 of the MID1 gene (1545delGA), resulting in a frameshift. A grandfather had hypertelorism, a history of swallowing difficulties as an infant, tracheoesophageal fistula, and anal atresia. A carrier daughter had telecanthus and epicanthic folds. Her son was noted at birth to have hypertelorism, cleft lip, laryngotracheal cleft, septal defect, and hypospadias. mutations MID1, 2-BP DEL, 1545GA number 8 clinvarAccessions RCV000011559;;1 status live name OPITZ SYNDROME, X-LINKED dbSnps rs387906719 text In a patient with Opitz syndrome ({300000}), {6:Ferrentino et al. (2007)} identified a 712G-T transversion in exon 2 of the MID1 gene, resulting in a glu238-to-ter (E238X) substitution. The mutant protein would lack the whole C-terminal region, resulting in a loss of function. {18:Zhang et al. (2011)} identified the E238X mutation in 2 Swedish brothers with hypospadias and hypertelorism, but no other features of Opitz syndrome. These authors suggested that hypospadias associated with hypertelorism is the mildest phenotype in Opitz syndrome caused by MID1 mutations. The mutation was not found in 95 controls. mutations MID1, GLU238TER number 9 clinvarAccessions RCV000022867;;1 prefix * titles alternativeTitles MIDLINE 1 RING FINGER GENE;; MIDIN;; FINGER ON X AND Y, MOUSE, HOMOLOG OF; FXY preferredTitle MIDLINE 1; MID1 textSectionList textSection textSectionTitle Description textSectionContent MID1 plays a role in the ubiquitin-specific regulation of the microtubule-associated catalytic subunit of protein phosphatase 2Ac (PP2AC; see {176915}), and a MID1/alpha-4 (IGBP1; {300139}) complex is the core of a microtubule-associated mRNP complex that links cytoskeleton-associated mRNA transport and translation control factors with members of the mTOR ({601231})/PP2A signaling cascade (summary by {1:Aranda-Orgilles et al., 2008}) textSectionName description textSectionTitle Cloning textSectionContent The study of a family in which the Opitz syndrome ({300000}) segregated with an X-chromosome inversion permitted {13:Quaderi et al. (1997)} to refine the position of the disease locus on Xp22, which they referred to as OSX (for Opitz syndrome, X-linked). By use of a positional cloning strategy within the OSX critical region, {14:Quaderi et al. (1997)} identified a novel gene, designated MID1 (midline-1), containing a RING finger motif. During their efforts to construct a transcription map of the Xp22 region, {14:Quaderi et al. (1997)} performed exon-trapping experiments on the cosmids contained in a previously described contig. One of the exon-trapping products was derived from the MID1 gene, which spans the Opitz syndrome inversion breakpoint. The MID1 protein belongs to a family of transcriptional regulators that contain protein-protein interaction domains and have been implicated in fundamental processes such as body axis patterning and cell transformation. The MID1 gene is ubiquitously expressed in both fetal and adult tissues and displays a transcript of approximately 7 kb that encodes a 667-amino acid protein. {4:Dal Zotto et al. (1998)} cloned the murine homolog of MID1. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal, and urogenital systems suggested that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. {4:Dal Zotto et al. (1998)} found that Mid1 is located within the mouse pseudoautosomal region in Mus musculus, whereas it seems to be X-specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and fluorescence in situ hybridization analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provided evidence that genetic instability of the PAR may affect functionally important genes. MID1 is the first example of a gene subject to X inactivation in man while escaping it in mouse. {11:Perry et al. (1998)} identified the 10-exon human FXY gene as a member of the RING finger family, characterized by the presence of an N-terminal zinc-binding domain. FXY also contains 4 additional domains: 2 potential zinc binding B box domains, a leucine coiled-coil domain characteristic of the 'RING B-box coiled-coil' (RBCC) subgroup of RING finger proteins, and a C-terminal domain conserved in several other RBCC proteins. {11:Perry et al. (1998)} determined that the human FXY cDNA encodes a 667-amino acid protein with 95% identity to the protein encoded by the mouse Fxy gene. A major RNA species of 7.4 kb and 2 minor RNAs of 4.3 and 2.6 kb were detected by Northern blot analysis in all adult human tissues tested. RT-PCR analysis demonstrated FXY expression in several 8- and 9-week human fetal tissues. {12:Pinson et al. (2004)} used in situ hybridization on human embryo sections to study MID1 expression during development. They found strong expression in the central nervous system, particularly the hindbrain, as well as in gastrointestinal and respiratory tract epithelium, metanephros, anal folds, and a small area of the interventricular septum of the heart. textSectionName cloning textSectionTitle Mapping textSectionContent {4:Dal Zotto et al. (1998)} refined the cytogenetic localization of the human MID1 gene to Xp22.3. {11:Perry et al. (1998)} demonstrated that the human FXY gene is located within Xp22.3, proximal to the human pseudoautosomal boundary. This finding provided further evidence for the addition-attrition theory ({7:Graves, 1995}), which proposes that divergence of the mammalian X and Y chromosomes has occurred through cyclical addition of autosomal segments onto the PAR of either the X or Y chromosome. The autosomal addition is then recombined onto its partner, resulting in an enlarged PAR. Meanwhile, the male-determining Y chromosome undergoes a series of rearrangements and deletions, reducing its homology with the X chromosome and gradually decreasing the size of the PAR as genes within this region lose their homologous Y-chromosome partner and become X-unique. The change in location of the STS gene from its presumed original PAR location to Xp22, proximal to the PAR, in humans has been presented as evidence for the addition-attrition theory. Southern blot hybridization analysis of male and female human genomic DNA demonstrated that FXY is probably X-linked; this was suggested by comparison of the signal obtained from DNA derived from the 2 sexes. To locate the gene more precisely, PCR primers derived from exon 2 were used to screen the Genebridge 4 radiation hybrid mapping panel. The localization to Xp22.3 was confirmed by mapping of an EST present in the Unigene database encompassing the 3-prime end of FXY. FXY was also mapped against 2 YAC contigs. They showed that the gene is flanked by 2 previously characterized genes, AMELX and CLCN4 ({302910}). textSectionName mapping textSectionTitle Gene Structure textSectionContent The MID1 gene contains 3 exons ({11:Perry et al., 1998}). {3:Cox et al. (2000)} showed that the MID1 gene spans at least 400 kb, almost twice the distance originally reported, and has a minimum of 6 mRNA isoforms as a result of the alternative use of 5-prime untranslated exons. textSectionName geneStructure textSectionTitle Gene Function textSectionContent {2:Cainarca et al. (1999)} referred to the protein encoded by the MID1 gene as midin. They stated that the putative 667-amino acid protein contains a so-called tripartite motif (a RING motif, 2 B-boxes, and a coiled-coil motif) and an RFP-like domain. The tripartite motif is characteristic of a family of proteins, named the B-box family, involved in cell proliferation and development. Since the subcellular compartment and the ability to form multiprotein structures both appear to be crucial for the function of this family of proteins, {2:Cainarca et al. (1999)} studied these properties on the wildtype and mutated forms of midin. They found that endogenous midin is associated with microtubules throughout the cell cycle, colocalizing with cytoplasmic fibers in interphase and with mitotic spindle and midbodies during mitosis and cytokinesis. Immunoprecipitation experiments demonstrated the ability of the tripartite motif to mediate midin homodimerization, consistent with the evidence, obtained by gel filtration analysis, that midin exists in the form of large protein complexes. Functional characterization of altered forms of midin, resulting from mutations found in Opitz syndrome patients, revealed that association with microtubules is compromised, while the ability to homodimerize and form multiprotein complexes is retained. Thus, {2:Cainarca et al. (1999)} suggested that midin is involved in the formation of multiprotein structures acting as anchor points to microtubules and that impaired association with these cytoskeletal structures causes the developmental defects of Opitz syndrome. (The RFP-like domain was first described in the RET finger protein (RFP; {602165}).) By using GFP as a tag, {15:Schweiger et al. (1999)} showed that MID1 is a microtubule-associated protein that influences microtubule dynamics in MID1-overexpressing cells. They confirmed this observation by demonstrating a colocalization of MID1 and tubulin (see {191130}) in subcellular fractions and the association of endogenous MID1 with microtubules after in vitro assembly. Furthermore, overexpressed MID1 proteins harboring mutations described in Opitz syndrome patients lack the capability to associate with microtubules, forming cytoplasmic clumps instead. These data gave an idea of the possible molecular pathomechanism underlying the Opitz syndrome phenotype. Wildtype Mid1 colocalizes predominantly with microtubules, in contrast to mutant versions of Mid1 that appear clustered in the cytosol. Using yeast 2-hybrid screening, {8:Liu et al. (2001)} found that the alpha-4 subunit (IGBP1; {300139}) of protein phosphatases-2A, -4, and -6 bound Mid1. Localization of Mid1 and the alpha-4 subunit was influenced by one another in transiently transfected cells. Mid1 could recruit the alpha-4 subunit onto microtubules, and high levels of the alpha-4 subunit could displace Mid1 into the cytosol. Metabolic (32)P labeling of cells revealed Mid1 to be a phosphoprotein, and coexpression of the full-length alpha-4 subunit decreased Mid1 phosphorylation, indicative of a functional interaction. Association of GFP-Mid1 with microtubules in living cells was perturbed by inhibitors of MAP kinase activation. {8:Liu et al. (2001)} concluded that Mid1 association with microtubules, which seems important for normal midline development, is regulated by dynamic phosphorylation involving MAP kinase and protein phosphatase that is targeted specifically to Mid1 by the alpha-4 subunit. Human birth defects may result from environmental or genetic disruption of this regulatory cycle. {1:Aranda-Orgilles et al. (2008)} found that MID1 associated with elongation factor-1-alpha (EF1A, or EEF1A1; {130590}) and several other proteins involved in mRNA transport and translation, including RACK1 (GNB2L1; {176981}), annexin A2 (ANXA2; {151740}), nucleophosmin (NPM1; {164040}), and proteins of the small ribosomal subunits. The cytoskeleton-bound MID1/translation factor complex, which also included alpha-4, specifically associated with G- and U-rich RNAs and incorporated MID1 mRNA, thus forming a microtubule-associated ribonucleoprotein complex. Mutant MID1 proteins found in Opitz syndrome patients lost the ability to interact with EF1A. textSectionName geneFunction textSectionTitle Evolution textSectionContent {9:Palmer et al. (1997)} identified a gene, which they symbolized Fxy for 'finger on X and Y,' that spans the mouse pseudoautosomal boundary on the X chromosome. The first 3 exons of the gene are located on the X chromosome, whereas the 3-prime exons of the gene are located on both the X and Y chromosomes. They proposed that the gene is at an intermediate stage in evolving from a pseudoautosomal location to one that is X-unique. The Fxy gene is identical to the Mid1 gene. {10:Perry and Ashworth (1999)} reported that in humans, the rat, and the wild mouse species Mus spretus, the FXY (MID1) gene is entirely X-unique. They found that the rate of sequence divergence of the 3-prime end of the Fxy gene is much higher when pseudoautosomal than when X-unique. They therefore suggested that chromosomal position can directly affect the rate of evolution of a gene. textSectionName evolution textSectionTitle Molecular Genetics textSectionContent {14:Quaderi et al. (1997)} identified mutations in the MID1 gene in 3 Opitz syndrome families: a 3-bp deletion involving a methionine codon ({300552.0001}), a 24-bp duplication causing addition of 8 amino acids ({300552.0002}), and a 1-bp insertion resulting in a frameshift and loss of 101 amino acid residues ({300552.0003}). All these mutations were in the C-terminal region of the MID1 gene. Among 15 patients with Opitz syndrome, {3:Cox et al. (2000)} identified 7 novel mutations in the MID1 gene, 2 of which disrupt the N terminus of the protein. The most severe of these, glu115 to ter (E115X; {300552.0005}), is predicted to truncate the protein before the B-box motifs. Another mutation, leu626 to pro (L626P; {300552.0004}), represented the most C-terminal alteration reported to date. Green fluorescent protein (GFP) fusion constructs of 2 N-terminal mutants showed no evidence of cytoplasmic aggregation, suggesting that this feature is not pathognomonic for X-linked Opitz syndrome. {12:Pinson et al. (2004)} identified 1 previously reported and 5 novel mutations in the MID1 gene in 14 patients with Opitz syndrome. Among 63 male individuals referred to {5:De Falco et al. (2003)} as instances of sporadic or familial X-linked Opitz syndrome, they found novel mutations of the MID1 gene in 11. The mutations were scattered throughout the gene, although more were represented in the 3-prime region. The low frequency of mutations in MID1 and the high variability of the phenotype suggested the involvement of other genes in the OS phenotype. {16:So et al. (2005)} identified 10 novel mutations in the MID1 gene in 70 patients with Opitz syndrome. textSectionName molecularGenetics geneMapExists true editHistory carol : 12/16/2011 ckniffin : 12/15/2011 alopez : 1/10/2011 mgross : 6/20/2008 terry : 5/27/2008 wwang : 4/13/2007 wwang : 8/26/2005 wwang : 8/24/2005 terry : 8/17/2005 carol : 8/9/2005 dateCreated Tue, 09 Aug 2005 03:00:00 EDT creationDate Victor A. McKusick : 8/9/2005 epochUpdated 1324022400 dateUpdated Fri, 16 Dec 2011 03:00:00 EST referenceList reference articleUrl http://dx.doi.org/10.1007/s00439-007-0456-6 publisherName Springer title The Opitz syndrome gene product MID1 assembles a microtubule-associated ribonucleoprotein complex. mimNumber 300552 referenceNumber 1 publisherAbbreviation Springer pubmedID 18172692 source Hum. Genet. 123: 163-176, 2008. authors Aranda-Orgilles, B., Trockenbacher, A., Winter, J., Aigner, J., Kohler, A., Jastrzebska, E., Stahl, J., Muller, E.-C., Otto, A., Wanker, E. E., Schneider, R., Schweiger, S. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10400985 publisherName HighWire Press title Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. mimNumber 300552 referenceNumber 2 publisherAbbreviation HighWire pubmedID 10400985 source Hum. Molec. Genet. 8: 1387-1396, 1999. authors Cainarca, S., Messali, S., Ballabio, A., Meroni, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11030761 publisherName HighWire Press title New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. mimNumber 300552 referenceNumber 3 publisherAbbreviation HighWire pubmedID 11030761 source Hum. Molec. Genet. 9: 2553-2562, 2000. authors Cox, T. C., Allen, L. R., Cox, L. L., Hopwood, B., Goodwin, B., Haan, E., Suthers, G. K. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9467009 publisherName HighWire Press title The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region. mimNumber 300552 referenceNumber 4 publisherAbbreviation HighWire pubmedID 9467009 source Hum. Molec. Genet. 7: 489-499, 1998. authors Dal Zotto, L., Quaderi, N. A., Elliott, R., Lingerfelter, P. A., Carrel, L., Valsecchi, V., Montini, E., Yen, C.-H., Chapman, V., Kalcheva, I., Arrigo, G., Zuffardi, O., Thomas, S., Willard, H. F., Ballabio, A., Disteche, C. M., Rugarli, E. I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.10265 publisherName John Wiley & Sons, Inc. title X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. mimNumber 300552 referenceNumber 5 publisherAbbreviation Wiley pubmedID 12833403 source Am. J. Med. Genet. 120A: 222-228, 2003. authors De Falco, F., Cainarca, S., Andolfi, G., Ferrentino, R., Berti, C., Rodriguez Criado, G.., Rittinger, O., Dennis, N., Odent, S., Rastogi, A., Liebelt, J., Chitayat, D., Winter, R., Jawanda, H., Ballabio, A., Franco, B., Meroni, G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.9480 publisherName John Wiley & Sons, Inc. title MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified. (Abstract) mimNumber 300552 referenceNumber 6 publisherAbbreviation Wiley pubmedID 17221865 source Hum. Mutat. 28: 206-207, 2007. Note: Full article online. authors Ferrentino, R., Bassi, M. T., Chitayat, D., Tabolacci, E., Meroni, G. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title The origin and function of the mammalian Y chromosome and Y-borne genes: an evolving understanding. mimNumber 300552 referenceNumber 7 pubmedID 7741724 source Bioessays 17: 311-320, 1995. authors Graves, J. A. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11371618 publisherName HighWire Press title Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha-4. mimNumber 300552 referenceNumber 8 publisherAbbreviation HighWire pubmedID 11371618 source Proc. Nat. Acad. Sci. 98: 6650-6655, 2001. authors Liu, J., Prickett, T. D., Elliott, E., Meroni, G., Brautigan, D. L. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9342357 publisherName HighWire Press title A gene spans the pseudoautosomal boundary in mice. mimNumber 300552 referenceNumber 9 publisherAbbreviation HighWire pubmedID 9342357 source Proc. Nat. Acad. Sci. 94: 12030-12035, 1997. authors Palmer, S., Perry, J., Kipling, D., Ashworth, A. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0960-9822(99)80430-8 publisherName Elsevier Science title Evolutionary rate of a gene affected by chromosomal position. mimNumber 300552 referenceNumber 10 publisherAbbreviation ES pubmedID 10508587 source Curr. Biol. 9: 987-989, 1999. authors Perry, J., Ashworth, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9425238 publisherName HighWire Press title The human FXY gene is located within Xp22.3: implications for evolution of the mammalian X chromosome. mimNumber 300552 referenceNumber 11 publisherAbbreviation HighWire pubmedID 9425238 source Hum. Molec. Genet. 7: 299-305, 1998. authors Perry, J., Feather, S., Smith, A., Palmer, S., Ashworth, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15121778 publisherName HighWire Press title Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome. (Letter) mimNumber 300552 referenceNumber 12 publisherAbbreviation HighWire pubmedID 15121778 source J. Med. Genet. 41: 381-386, 2004. authors Pinson, L., Auge, J., Audollent, S., Mattei, G., Etchevers, H., Gigarel, N., Razavi, F., Lacombe, D., Odent, S., Le Merrer, M., Amiel, J., Munnich, A., Meroni, G., Lyonnet, S., Vekemans, M., Attie-Bitach, T. pubmedImages false publisherUrl http://highwire.stanford.edu source Am. J. Hum. Genet. 61 (suppl.): A10 only, 1997. mimNumber 300552 authors Quaderi, N. A., Schweiger, S., Gaudenz, K., Franco, B., Rugarli, E., Feldman, G. J., Volta, M., Gilgenkrantz, S., Berger, W., Opitz, J., Muencke, J., Ropers, H., Ballabio, A. title Opitz syndrome, a defect of midline development, is due to mutations in a novel RING finger gene on Xq22. (Abstract) referenceNumber 13 articleUrl http://dx.doi.org/10.1038/ng1197-285 publisherName Nature Publishing Group title Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. mimNumber 300552 referenceNumber 14 publisherAbbreviation NPG pubmedID 9354791 source Nature Genet. 17: 285-291, 1997. authors Quaderi, N. A., Schweiger, S., Gaudenz, K., Franco, B., Rugarli, E. I., Berger, W., Feldman, G. J., Volta, M., Andolfi, G., Gilgenkrantz, S., Marion, R. W., Hennekam, R. C. M., Opitz, J. M., Muenki, M., Ropers, H. H., Ballabio, A. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10077590 publisherName HighWire Press title The Opitz syndrome gene product, MID1, associates with microtubules. mimNumber 300552 referenceNumber 15 publisherAbbreviation HighWire pubmedID 10077590 source Proc. Nat. Acad. Sci. 96: 2794-2799, 1999. authors Schweiger, S., Foerster, J., Lehmann, T., Suckow, V., Muller, Y. A., Walter, G., Davies, T., Porter, H., van Bokhoven, H., Lunt, P. W., Traub, P., Ropers, H.-H. pubmedImages true publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.30407 publisherName John Wiley & Sons, Inc. title Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. mimNumber 300552 referenceNumber 16 publisherAbbreviation Wiley pubmedID 15558842 source Am. J. Med. Genet. 132A: 1-7, 2005. authors So, J., Suckow, V., Kijas, Z., Kalscheuer, V., Moser, B., Winter, J., Baars, M., Firth, H., Lunt, P., Hamel, B., Meinecke, P., Moraine, C., {and 14 others} pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1007/s00439-002-0901-5 publisherName Springer title Duplication of the MID1 first exon in a patient with Opitz G/BBB syndrome. mimNumber 300552 referenceNumber 17 publisherAbbreviation Springer pubmedID 12545276 source Hum. Genet. 112: 249-254, 2003. authors Winter, J., Lehmann, T., Suckow, V., Kijas, Z., Kulozik, A., Kalscheuer, V., Hamel, B., Devriendt, K., Opitz, J., Lenzner, S., Ropers, H.-H., Schweiger, S. pubmedImages false publisherUrl http://www.springeronline.com/ title Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome. mimNumber 300552 referenceNumber 18 pubmedID 21326312 source J. Hum. Genet. 56: 348-351, 2011. authors Zhang, X., Chen, Y., Zhao, S., Markljung, E., Nordenskjold, A. pubmedImages false externalLinks cmgGene false mgiHumanDisease false nextGxDx true ncbiReferenceSequences 300797069,300797196,300797214,530421145,300797049,530421147,300797131,300797028,530421143,300797174,300797110,300797152 nbkIDs NBK1327;;X-Linked Opitz G/BBB Syndrome;;;NBK5192;;Esophageal Atresia/Tracheoesophageal Fistula Overview dermAtlas false hprdIDs 02047 swissProtIDs O15344 zfinIDs ZDB-GENE-110411-205 uniGenes Hs.27695,Hs.460482,Hs.738954,Hs.689953 refSeqAccessionIDs NG_008197.1 gtr true ensemblIDs ENSG00000101871,ENST00000317552 umlsIDs C1417167 genbankNucleotideSequences 148121300,478414724,148121301,148121302,6143839,148121303,146107062,148121296,148121297,2935593,148121298,148121299,148121308,478414732,148121309,148121310,148121311,148121304,148121305,529602460,148121306,148121307,148121284,148121285,148121286,148121287,148121280,1553155,148121281,148121282,148121283,148121292,167773208,148121293,148121294,148121295,148121288,148121289,148121290,148121291,2612792,146131860,148121328,148121329,148121330,148121331,56266864,148121316,148121317,148121318,46254579,148121319,148121312,46254581,56266862,148121313,46254580,56266863,148121314,148121315,148121324,148121325,15799496,46254584,148121326,46254587,148121327,46254586,148121320,46254589,148121321,5656683,46254588,148121322,46254591,148121323,46254590,110624725,31565477,221042529,3462502,4149864,164693897,3462510,157678649,157678648,3462506,157678650,80847024,551893382,551893389,551893384,551893387,12275915,12275913,33589124,33589125,33589129,10437650,2411434,71517132,11228708,158255865,2809270,511786279,511786278,511786281,511786280,511786282,46254593,21622667,46254595,46254594,46254597,46254596,46254599,46254598,46254601,46254600,46254603,46254602,46254605,46254604,46254607,46254606,46254608,46254611,146218341,46254610,146218340,46254613,146218339,46254612,146218338,46254615,46254614,46254617,46254616,46254619,46254618,82159678,46254621,194386251,46254620,46254622,46254625,46254624,46254627,46254626,46254629,46254628,46254631,46254630,46254633,46254632,46254635,46254634,46254637,46254639,46254638,46254640,2827993 geneTests true approvedGeneSymbols MID1 geneIDs 4281 proteinSequences 530421148,148833499,530421144,31565478,530421146,300797153,11228709,221042530,578837902,119619185,578837904,119619187,119619186,3462503,158255866,167773209,194386252,300797175,300797111,3462511,2612793,3462507,300797197,300797132,15451852,22653810,2827994,12275914,189054709,300797215,12275916,4557753 geneticsHomeReferenceIDs gene;;MID1;;MID1 locusSpecificDBs http://www.LOVD.nl/MID1;;MID1 database at LOVD

entryList

entry status live allelicVariantExists true epochCreated 646902000 geneMap geneSymbols MBL2, MBL, MBP1, MBL2D, MBPD sequenceID 7445 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 154545 phenotypeInheritance None phenotype {Chronic infections, due to MBL deficiency} phenotypeMimNumber 614372 chromosomeLocationStart 54525139 chromosomeSort 173 chromosomeSymbol 10 mimNumber 154545 geneInheritance None confidence C mappingMethod REa, A, Fd geneName Mannose-binding lectin 2, soluble (opsonic defect) comments near MEN2A mouseMgiID MGI:96924 mouseGeneSymbol Mbl2 computedCytoLocation 10q21.1 cytoLocation 10q11.2-q21 transcript uc001jjt.3 chromosomeLocationEnd 54532577 chromosome 10 contributors Paul J. Converse - updated : 6/16/2011 Cassandra L. Kniffin - updated : 6/2/2008 Marla J. F. O'Neill - updated : 6/7/2007 Paul J. Converse - updated : 11/1/2006 Marla J. F. O'Neill - updated : 10/17/2006 Paul J. Converse - updated : 8/4/2006 John A. Phillips, III - updated : 4/4/2006 Paul J. Converse - updated : 1/6/2006 Paul J. Converse - updated : 8/15/2005 Marla J. F. O'Neill - updated : 11/3/2004 Cassandra L. Kniffin - reorganized : 8/26/2004 Cassandra L. Kniffin - updated : 8/25/2004 Paul J. Converse - updated : 11/2/2001 Michael J. Wright - updated : 6/5/2001 Victor A. McKusick - updated : 4/25/2001 Paul J. Converse - updated : 4/12/2001 George E. Tiller - updated : 10/17/2000 Ada Hamosh - updated : 9/13/2000 Victor A. McKusick - updated : 12/22/1999 Victor A. McKusick - updated : 10/11/1999 Victor A. McKusick - updated : 6/3/1999 clinicalSynopsisExists false mimNumber 154545 allelicVariantList allelicVariant status live name MANNOSE-BINDING PROTEIN DEFICIENCY dbSnps rs1800450 text In 3 unrelated children with recurrent infections, opsonization defect, and low serum MBP protein concentrations ({614372}), {27:Sumiya et al. (1991)} identified a homozygous 230G-A transition in the MBL2 gene, resulting in a gly54-to-asp (G54D) substitution. The change is known as the 'B' allele. The change occurs in the fifth collagen repeat of the protein, which the authors predicted may disrupt the collagen helix sufficiently to hinder MBL assembly and secretion by hepatocytes. Study of 16 members of the 3 families showed autosomal dominant co-inheritance of the G54D mutation and low serum MBP concentrations. {29:Super et al. (1992)} found that among more than 100 randomly selected patients 5% were homozygotes for asp54. They showed that recombinant MBL with the asp54 substitution can oligomerize to yield a functional protein of about 650 kD that binds ligand and functions as an opsonin. However, although the recombinant MBL could form hexamers and therefore, like serum MBL, would be expected to act as a surrogate for C1q in classical pathway activation, this function was defective. The results indicated that the G54D substitution does not account for a deficiency state, but instead suggested that MBL has 2 predominant allelic forms that have overlapping function and that differ only in their ability to activate the classical pathway of complement. By immunoassay, {16:Lipscombe et al. (1992)} found reduced serum MBP levels in individuals carrying the G54D change. However, 3 wildtype individuals had no detectable MBP protein. The G54D change showed a reduced capacity to activate complement through the MPB-initiated classical pathway. The authors suggested that both homozygous and heterozygous individuals would have reduced serum levels of the protein. In a study of 123 healthy Danish individuals, {11:Garred et al. (1992)} found that 93 (75.6%) were gly54 homozygotes, 28 (22.8%) were heterozygous, and 2 (1.6%) were asp54 homozygotes; the frequency of the asp54 allele was 0.13. The median MBL concentration in the group of subjects with the asp54 allele was 6.4 times lower than in the gly54 homozygous group (195 and 1234 microg/l, respectively); however, the range in plasma concentrations of MBL was wide and overlapped between the groups. MBL protein was detected in the 2 asp54 homozygotes (9 and 387 microg/L), and there was no difference in relative mass and biologic activity between the 2 forms of the protein. {11:Garred et al. (1992)} concluded that the asp54 allele is able to produce a functional MBL protein that can be detected in serum at low concentrations. In 2 adult patients with severe and unusual infections, {28:Summerfield et al. (1995)} identified homozygosity for the G54D change. A third patient was compound heterozygous for the G54D and R52C ({154545.0003}) changes. The authors concluded that MBP deficiency may confer a life-long risk of infection. {32:Turner et al. (2000)} used MBL polymorphisms in the indigenous Australian population to date the appearance of the MBL B allele. They found a paucity of MBL structural gene mutations in 2 population groups from geographically distinct regions. Of 293 individuals tested, 289 were wildtype, and 4 were heterozygous for either the B or D allele. In each individual with an MBL mutation, the HLA haplotype profile suggested some Caucasian admixture. The authors hypothesized that the B mutation probably arose between 50,000 and 20,000 years ago, and that its absence from the founder gene pool of indigenous Australians may also partly explain their vulnerability to intracellular infections such as tuberculosis. To test the hypothesis that a genetic predisposition to a proinflammatory state could favor the appearance of gestational diabetes mellitus (GDM), {19:Megia et al. (2004)} studied the R52C ({154545.0003}) and G54D polymorphisms of the MBL2 gene and plasma MBL levels from 105 consecutive women with GDM and 173 healthy pregnant women. They found an association between G54D and GDM (odds ratio = 2.03 (1.18-3.49); P less than 0.01), and this association remained significant when the presence of both mutated alleles was considered (odds ratio = 1.76 (1.04-2.96); P less than 0.05). GDM patients who carried the G54D mutation required insulin therapy more frequently and had heavier infants than GDM women homozygous for the wildtype allele. An inverse correlation in GDM patients between neonatal weight and plasma MBL levels was found, remaining significant after adjustment for confounding variables. mutations MBL2, GLY54ASP number 1 clinvarAccessions RCV000015424;;1 status live name MANNOSE-BINDING PROTEIN DEFICIENCY dbSnps rs1800451 text In Gambians from West Africa, {16:Lipscombe et al. (1992)} identified a G-to-A transition in exon 1 of the MBL2 gene, resulting in a gly57-to-glu (G57E) substitution. The change is known as the 'C' allele. Like the G54D ({154545.0001}) mutation, the substitution of a carboxylic acid for an axial glycine in the translated protein would be expected to disrupt the secondary structure of the collagenous triple helix of the MBL subunits. The serum MBP values in Gambians heterozygous for the mutation were significantly lower ({614372}) than values in wildtype individuals. mutations MBL2, GLY57GLU number 2 clinvarAccessions RCV000015425;;1 status live name MANNOSE-BINDING PROTEIN DEFICIENCY dbSnps rs5030737 text {17:Madsen et al. (1994)} identified a third variant allele, the 'D' allele ({dbSNP rs5030737}), in the collagen region of MBL2, and suggested that this variant could explain cases of MBL2 deficiency ({614372}) not determined by the other variants. The frequency of allele D was 0.05 in both African and Caucasian populations, but the allele was absent in Eskimos. {1:Bodamer et al. (2006)} genotyped 5 common polymorphisms, including the B, C, and D variants, of the MBL2 gene in 102 infants born before 36 weeks' gestation and 102 infants born at full term and found that the frequency of the D allele was significantly higher in preterm infants compared to term infants (p = 0.04). mutations MBL2, ARG52CYS number 3 clinvarAccessions RCV000015426;;1 prefix * titles alternativeTitles MANNOSE-BINDING LECTIN; MBL;; MANNOSE-BINDING PROTEIN, SERUM; MBP1;; MANNAN-BINDING PROTEIN;; COLLECTIN 1; COLEC1 preferredTitle LECTIN, MANNOSE-BINDING, SOLUBLE, 2; MBL2 textSectionList textSection textSectionTitle Description textSectionContent The MBL2 gene encodes a mannose-binding lectin (MBL), or protein (MBP), that is secreted by the liver as part of the acute-phase response and is involved in innate immune defense. The ligands for MBL are expressed by a wide variety of microorganisms, and binding of the protein leads to opsonization as well as activation of the complement system ({20:Ohlenschlaeger et al., 2004}). textSectionName description textSectionTitle Cloning textSectionContent From a human liver cDNA library, {6:Ezekowitz et al. (1988)} isolated a cDNA clone corresponding to a mannose-binding protein. The deduced 248-amino acid protein contains an N-terminal cysteine-rich segment, a collagen-like domain, a 'neck' region, and a C-terminal putative carbohydrate-binding domain. The human MBP protein showed approximately 50% homology to the 2 rodent mannose-binding proteins, MbpA and MbpC. {30:Taylor et al. (1989)} showed that the N-terminal sequence of the major human serum mannose-binding protein is identical at all positions determined with the amino acid sequence predicted from a cDNA clone of the human liver MBL mRNA. {30:Taylor et al. (1989)} determined that each of the 3 MBP domains is encoded by a separate exon, which is consistent with evolution by a process of exon shuffling. Identical MBP chains of 32 kD associated to form trimers of 96 kD, and these assemble into higher oligomers which circulate in serum. Consensus sequences in the promoter region of the gene are consistent with MBP being an acute-phase protein synthesized by the liver. textSectionName cloning textSectionTitle Gene Structure textSectionContent {30:Taylor et al. (1989)} determined that the MBP gene contains 4 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent {23:Sastry et al. (1989)} assigned the MBL gene to chromosome 10q11.2-q21 by a combination of Southern analysis of somatic cell hybrids and in situ hybridization. {24:Schuffenecker et al. (1991)} confirmed the assignment to 10q11.2-q21 by in situ hybridization. They described a RFLP and used it to show that the MBL locus is close to the MEN2A locus ({171400}). By interspecies backcross analysis, {33:White et al. (1994)} mapped the gene for murine MbpA (Mbl1) to chromosome 14, a region homologous to human chromosome 10. The mRNA corresponding to MbpA, but not MbpC, is elevated in response to stimuli known to induce acute phase response. Pseudogene Using PCR, {12:Guo et al. (1998)} detected low level expression of an MBP pseudogene, which they called MBL1P1, in liver. The pseudogene encodes a truncated 51-amino acid protein that is homologous to the Mbpa isoform in rodents and primates. By FISH, they mapped the pseudogene to 10q22.2-q22.3. textSectionName mapping textSectionTitle Gene Function textSectionContent {4:Dean et al. (2010)} used whole-blood cultures stimulated with zymosan (Zy) or MBL-opsonized zymosan (MBL-Zy) of MBL-deficient (see {614372}) or -sufficient individuals and measured intracellular cytokine expression. They found that MBL-deficient individuals produced significantly more IL6 ({147620}) and TNF ({191160}) in response to Zy, whereas these individuals produced significantly less IL6 in response to MBL-Zy. Both MLBL-sufficient and -deficient individuals upregulated CD83 ({604534}) expression and downregulated CXCR4 ({162643}), CD62L (SELL; {153240}), CD49D (ITGA4; {192975}), CD40 ({109535}), and CD86 ({601020}) expression in response to Zy and MBL-Zy. Allogeneic proliferative, but not effector, responses were identical between the 2 groups. {4:Dean et al. (2010)} concluded that MBL deficiency is associated with unique functional characteristics of pathogen-stimulated blood myeloid dendritic cells, particularly increased IL6 production. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent MBP Deficiency and Susceptibility To and Recovery From Infection {28:Summerfield et al. (1995)} challenged the prevailing view that although MBP deficiency ({614372}) causes recurrent infections in infants between 6 and 18 months of age, it does not predispose to adult infections. They described 4 patients with severe and unusual infections in which MBP gene mutations (G54D; {154545.0001} and G57E; {154545.0002}) were the only identified cause of immunodeficiency, and 1 patient with combined MBP and IgA deficiency. Two patients were homozygous for codon 54 mutations, 1 patient was compound heterozygous for both mutations, and 2 patients were heterozygous for codon 54 mutations. {9:Garred et al. (1995)} investigated the frequency of 3 abnormal MBP alleles ({154545.0001}-{154545.0003}), each of which has a dominant effect on MBP concentration, in 228 unrelated patients referred to their laboratory over a 3-year period for immunologic investigation of various non-HIV-related immunodeficiencies. Frequency of heterozygotes for the abnormal alleles was not different from that in the background population (36% and 37.4%, respectively). By contrast, the frequency of homozygotes for the abnormal alleles was significantly increased (8.3% and 0.8%, respectively; p = 0.0017). {9:Garred et al. (1995)} suggested that homozygotes for abnormal MBP alleles are predisposed to recurrent infections. {8:Garred et al. (1997)} found that a significantly higher number of HIV-infected homosexual males were homozygous for variant MBL2 alleles than were high-risk homosexual controls or healthy controls. Although no significant association was found in progression from infection to clinical AIDS, there was a significantly shorter mean survival time after AIDS diagnosis in men carrying variant MBL2 alleles and those with low serum MBL. The authors suggested that the increased risks may be associated with increased susceptibility to coinfections. {15:Jack et al. (1997)} described a rapid and simple method for genotyping the 3 known structural mutations within exon 1 of the MBL gene. {13:Hibberd et al. (1999)} studied the association of these 3 variants (at codons 52, 54, and 57 of exon 1 of the MBL gene) in relation to susceptibility to meningococcal disease. They found homozygosity or compound heterozygosity for these 3 alleles in 1.5 to 2.7% of controls and in 7.7 to 8.3% of subjects with meningococcal disease. {25:Soborg et al. (2003)} examined MBL genotypes and serum MBL levels in 109 patients with clinical tuberculosis (see {607948}) and 250 controls. Heterozygotes with a variant MBL structural allele associated with low functional serum MBL on one chromosome and a normal MBL structural allele with a low-expression promoter polymorphism on the other chromosome appeared to be relatively protected against clinical tuberculosis, whereas genotypes associated with high MBL expression and genotypes conferring MBL deficiency were not. {25:Soborg et al. (2003)} proposed that low serum MBL may be protective against tuberculosis by limiting complement activation and uptake of bacilli by complement receptors. In the absence of MBL, bacilli may be taken up directly by mannose receptors (e.g., MRC1; {153618}). {31:Thio et al. (2005)} genotyped 2 promoter SNPs and 3 exon 1 SNPs in the MBL2 gene in a large cohort of individuals with either hepatitis B virus (HBV; see {610424}) persistence or recovery. They found that a promoter SNP, -221G-C, which leads to deficient MBL production, was more common in subjects with HBV persistence. Individuals homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had highly increased odds of recovery from infection. In contrast, those homozygous for the combination of promoter and exon 1 genotypes associated with the lowest amount of functional MBL were more likely to have viral persistence. MBP Deficiency and Cystic Fibrosis Because MBL is a key factor in innate immunity, and lung infections are a leading cause of morbidity and mortality in cystic fibrosis (CF; {219700}), {10:Garred et al. (1999)} investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, {10:Garred et al. (1999)} estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. {3:Davies et al. (2000)} found that MBL binds to Burkholderia cepacia, an important pathogen in patients with CF, and leads to complement activation, but that this was not the case for Pseudomonas aeruginosa, the more common colonizing organism in CF. {3:Davies et al. (2000)} suggested that patients with CF and mannose-binding lectin deficiency would be at a particularly high risk of B. cepacia colonization. The lack of binding to P. aeruginosa suggests that the effect of this organism on lung function in patients with MBL-deficient CF reflects a role for MBL, either in intercurrent infections with other organisms, or in the inflammatory process. {7:Gabolde et al. (2001)} showed that the presence of cirrhosis in patients with cystic fibrosis is significantly associated with either homozygous or compound heterozygous mutant mannose-binding lectin. In an association study involving 112 patients with cystic fibrosis, {34:Yarden et al. (2004)} found that patients with the MBL2 A/O or O/O genotypes were more likely to have a more severe pulmonary phenotype than patients with the A/A genotype (p = 0.002). No association was found between the MBL2 genotype and the age at first infection with P. aeruginosa. {34:Yarden et al. (2004)} concluded that it is very likely that MBL2 is a modulating factor in CF. {2:Buranawuti et al. (2007)} determined the MLB2 A/O genotype in 3 groups of patients with CF: 101 children under 17 years of age, 115 adults, and 38 nonsurviving adults (21 deceased and 17 lung transplant after 17 years of age). Genotype frequencies among adults and children with CF differed for MBL2 (A/A vs O/O, p = 0.016), suggesting that MBL2 O/O is associated with reduced survival beyond 17 years of age. When adults with CF were compared to nonsurviving adults with CF, genotype frequencies again differed (MBL2 A/A vs O/O, p = 0.009), and the hazard ratio for MLB2 O/O versus A/A or A/O was 2.5. {2:Buranawuti et al. (2007)} concluded that the MBL2 O/O genotype appears to be a genetic modifier of survival in patients with CF. In a study of 1,019 Canadian pediatric CF patients, {5:Dorfman et al. (2008)} found a significant association between earlier age of first P. aeruginosa infection and MBL2 deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). Low and intermediate MBL2 groups included combinations of the G54D, G57E, and R52C alleles. This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10 ({190180.0007}). MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TGFB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function. MBP Deficiency and Vascular Disease Among 76 Norwegian patients with severe atherosclerotic disease, {18:Madsen et al. (1998)} found that 13.2% of the patients were homozygous for the MBL O/O genotype, O being the common designation for the variant alleles B ({154545.0001}), C ({154545.0002}), and D ({154545.0003}) at codons 54, 57, and 52, respectively. Three percent of normal controls had the O/O genotype. There was a trend toward homozygous MBL-defective patients being younger than those patients carrying 1 or 2 copies of the wildtype gene, suggesting that the MBL-deficient patients may have earlier disease onset or a more progressive disease course. {18:Madsen et al. (1998)} noted that ischemic heart disease is a multifactorial disease that has been associated with Chlamydia pneumoniae infection. Cardiovascular disease is a major cause of illness and death in patients with systemic lupus erythematosus (SLE; {152700}). In an MBP genotype study of 91 Danish patients with SLE, {20:Ohlenschlaeger et al. (2004)} found that 54 (59%) were wildtype A/A, 30 (33%) were A/O, and 7 (8%) were O/O MBP genotypes. The A allele refers to the wildtype alleles at codons 54, 57, and 52. During a median follow-up period of 9 years, arterial thrombosis developed in 6 of the 7 patients with the O/O genotype compared to 18 of the 84 patients with the A/A or A/O genotypes (odds ratio 7.0). The increased risk of thrombosis was particularly pronounced for myocardial infarction. There was no association between MBP genotype and venous thromboses. MBP Deficiency and Gestational Diabetes Mellitus {19:Megia et al. (2004)} found an association between the G54D polymorphism ({154545.0001}) and gestational diabetes mellitus (GDM). MBP Deficiency and Preterm Delivery {1:Bodamer et al. (2006)} genotyped 5 common polymorphisms, including the B, C, and D variants, of the MBL2 gene in 102 infants born before 36 weeks' gestation and 102 infants born at full term and found that the frequency of the D allele was significantly higher in preterm infants compared to term infants (p = 0.04). textSectionName molecularGenetics textSectionTitle Inheritance textSectionContent By analysis of same-sex monozygotic and dizygotic twins aged 6 to 9 years, {14:Husby et al. (2002)} estimated the heritability of serum concentrations of the collectins SPD ({178635}) and MBL to be 0.91 and 0.96, respectively. The data indicated that there is a strong genetic, rather than environmental, dependence for serum levels of SPD and MBL. textSectionName inheritance textSectionTitle Population Genetics textSectionContent In Gambians from West Africa, {16:Lipscombe et al. (1992)} determined that the frequency of the G57E ({154545.0002}) change in the MBP gene was 0.29 in adults and 0.23 in newborns, whereas the frequency of the G54D change was very rare, at 0.003. The G54D mutation was more common in both a British Caucasian and a Hong Kong Chinese population (frequency 0.17 and 0.11, respectively). The frequency data suggested that the change at codon 57 presumably arose after the separation between Africans and non-Africans approximately 100,000-150,000 years ago. The mutation at codon 54 may have occurred more than 40,000 years ago before the divergence of European Caucasoids from the ancestral Chinese. Both mutations have obtained high frequencies in their respective populations. With the evolution of the adaptive antibody response, the major role of mannose-binding protein in immunity may be restricted in man to the 'window of vulnerability' in early life. The increased susceptibility to pediatric infection of a small number of homozygotes with these mutations may be outweighed by an advantage enjoyed by both homozygotes and heterozygotes of a reduced capacity for complement activation and possible immunopathologically mediated host damage. {22:Ross and Densen (1984)} noted the low mortality associated with meningococcal disease in complement-deficient individuals and suggested that tissue damage resulting from activation of complement by endotoxin may be reduced in such individuals. Similarly, {21:Orren et al. (1987)} reported a high frequency of C6 deficiency ({612446}) in the mixed race and black populations of South Africa and suggested that the deficiency may be beneficial in infancy by limiting the incidence of septicemic shock. Thus this may be a balanced polymorphism like that of sickle hemoglobin. textSectionName populationGenetics textSectionTitle Evolution textSectionContent From the structure of the MBL gene, {23:Sastry et al. (1989)} concluded that it evolved by recombination of an ancestral nonfibrillar collagen gene with a gene that encodes carbohydrate recognition. Similarities to the human surfactant gene SFTP1 ({178630}), which maps to approximately the same area, were noted. Rodents have 2 forms of mannose-binding protein, MbpA (Mbl1) and MbpC (Mbl2), that share a high degree of homology to each other and are therefore likely to be products of a gene duplication event. {33:White et al. (1994)} mapped the murine Mbl1 and Mbl2 genes to chromosomes 14 and 19, respectively. If the gene duplication event occurred before the divergence of rodents and humans, one would expect to find a second human MBL gene. Since the murine Mbl2 gene is closely linked to the relaxin locus (RLN1; {179730}), {33:White et al. (1994)} suggested that a second putative MBL gene in the human, if it exists, may be located on chromosome 9 near the relaxin gene. However, the authors noted that there are examples of genes that are single in the human and duplicate in the mouse, or vice versa, insulin being one example. textSectionName evolution textSectionTitle Animal Model textSectionContent Using fluorescence microscopy and flow cytometry, {26:Stuart et al. (2005)} found that recombinant MBL, independently of any contaminating antibody, bound not only to dying cells, but also to certain live cells in vitro. Mice deficient in Mbl were significantly less able to clear apoptotic cells. Mbl -/- mice had increased numbers of B1 cells, a subpopulation of B cells that produce natural antibodies with low affinity for certain bacteria and self-antigens. However, Mbl -/- mice exhibited no germinal center expansion, lymphoproliferation, or any signs of increased autoimmunity, even when crossed with autoimmune-prone mice. {26:Stuart et al. (2005)} concluded that MBL is important for clearance of apoptotic cells, but failure of apoptotic cell clearance is dissociated from autoimmunity. textSectionName animalModel geneMapExists true editHistory carol : 04/22/2013 terry : 4/1/2013 terry : 6/6/2012 mgross : 12/15/2011 mgross : 12/2/2011 terry : 6/16/2011 carol : 4/25/2011 terry : 1/30/2009 wwang : 6/17/2008 ckniffin : 6/2/2008 wwang : 6/13/2007 terry : 6/7/2007 mgross : 11/1/2006 wwang : 10/19/2006 terry : 10/17/2006 mgross : 8/30/2006 terry : 8/4/2006 alopez : 4/4/2006 mgross : 1/6/2006 mgross : 8/15/2005 tkritzer : 11/11/2004 tkritzer : 11/4/2004 terry : 11/3/2004 carol : 8/26/2004 ckniffin : 8/25/2004 mgross : 3/10/2003 joanna : 1/31/2002 mgross : 11/2/2001 mgross : 11/2/2001 alopez : 6/5/2001 alopez : 6/5/2001 cwells : 5/3/2001 mcapotos : 5/2/2001 mcapotos : 4/26/2001 terry : 4/25/2001 mgross : 4/12/2001 alopez : 10/17/2000 alopez : 10/3/2000 terry : 9/13/2000 mcapotos : 1/10/2000 mcapotos : 1/4/2000 terry : 12/22/1999 mgross : 10/11/1999 alopez : 6/21/1999 jlewis : 6/15/1999 terry : 6/3/1999 alopez : 2/26/1999 carol : 10/29/1998 terry : 1/21/1997 mark : 2/19/1996 terry : 2/16/1996 mark : 5/19/1995 carol : 2/17/1995 carol : 6/28/1993 carol : 5/28/1993 carol : 5/26/1993 carol : 2/17/1993 dateCreated Mon, 02 Jul 1990 03:00:00 EDT creationDate Victor A. McKusick : 7/2/1990 epochUpdated 1366614000 dateUpdated Mon, 22 Apr 2013 03:00:00 EDT referenceList reference articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1098-3600&volume=8&issue=8&spage=518 publisherName Lippincott Williams & Wilkins title Evidence for an association between mannose-binding lectin 2 (MBL2) gene polymorphisms and pre-term birth. mimNumber 154545 referenceNumber 1 publisherAbbreviation LWW pubmedID 16912583 source Genet. Med. 8: 518-524, 2006. authors Bodamer, O. A., Mitterer, G., Maurer, W., Pollak, A., Mueller, M. W., Schmidt, W. M. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=17158822 publisherName HighWire Press title Variants in mannose-binding lectin and tumour necrosis factor alpha affect survival in cystic fibrosis. mimNumber 154545 referenceNumber 2 publisherAbbreviation HighWire pubmedID 17158822 source J. Med. Genet. 44: 209-214, 2007. authors Buranawuti, K., Boyle, M. P., Cheng, S., Steiner, L. L., McDougal, K., Fallin, M. D., Merlo, C., Zeitlin, P. L., Rosenstein, B. J., Mogayzel, P. J., Jr., Wang, X., Cutting, G. R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(00)02297-2 publisherName Elsevier Science title Differential binding of mannose-binding lectin to respiratory pathogens in cystic fibrosis. mimNumber 154545 referenceNumber 3 publisherAbbreviation ES pubmedID 10866448 source Lancet 355: 1885-1886, 2000. authors Davies, J., Neth, O., Alton, E., Klein, N., Turner, M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1111/j.1365-2567.2010.03365.x publisherName Blackwell Publishing title Mannose-binding lectin deficiency influences innate and antigen-presenting functions of blood myeloid dendritic cells. mimNumber 154545 referenceNumber 4 publisherAbbreviation Blackwell pubmedID 21091907 source Immunology 132: 296-305, 2010. authors Dean, M. M., Flower, R. L., Eisen, D. P., Minchinton, R. M., Hart, D. N. J., Vuckovic, S. pubmedImages true publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1172/JCI33754 publisherName Journal of Clinical Investigation title Complex two-gene modulation of lung disease severity in children with cystic fibrosis. mimNumber 154545 referenceNumber 5 publisherAbbreviation JCI pubmedID 18292811 source J. Clin. Invest. 118: 1040-1049, 2008. authors Dorfman, R., Sandford, A., Taylor, C., Huang, B., Frangolias, D., Wang, Y., Sang, R., Pereira, L., Sun, L., Berthiaume, Y., Tsue, L.-C., Pare, P. D., Durie, P., Corey, M., Zielenski, J. pubmedImages true publisherUrl http://www.jci.org title A human mannose-binding protein is an acute phase reactant that shares sequence homology with other vertebrate lectins. mimNumber 154545 referenceNumber 6 pubmedID 2450948 source J. Exp. Med. 167: 1034-1046, 1988. Note: Erratum: J. Exp. Med. 174: 753 only, 1991. authors Ezekowitz, R. A., Day, L. E., Herman, G. A. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=11333866 publisherName HighWire Press title The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis. mimNumber 154545 referenceNumber 7 publisherAbbreviation HighWire pubmedID 11333866 source J. Med. Genet. 38: 310-311, 2001. authors Gabolde, M., Hubert, D., Guilloud-Bataille, M., Lenaerts, C., Feingold, J., Besmond, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(96)08440-1 publisherName Elsevier Science title Susceptibility to HIV infection and progression of AIDs in relation to variant alleles of mannose-binding lectin. mimNumber 154545 referenceNumber 8 publisherAbbreviation ES pubmedID 9014910 source Lancet 349: 236-240, 1997. authors Garred, P., Madsen, H. O., Balslev, U., Hofmann, B., Pedersen, C., Gerstoft, J., Svejgaard, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(95)91559-1 publisherName Elsevier Science title Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency. mimNumber 154545 referenceNumber 9 publisherAbbreviation ES pubmedID 7564730 source Lancet 346: 941-943, 1995. authors Garred, P., Madsen, H. O., Hofmann, B., Svejgaard, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI6861 publisherName Journal of Clinical Investigation title Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. mimNumber 154545 referenceNumber 10 publisherAbbreviation JCI pubmedID 10449435 source J. Clin. Invest. 104: 431-437, 1999. authors Garred, P., Pressler, T., Madsen, H. O., Frederiksen, B., Svejgaard, A., Hoiby, N., Schwartz, M., Koch, C. pubmedImages true publisherUrl http://www.jci.org title Gene frequency and partial protein characterization of an allelic variant of mannan binding protein associated with low serum concentrations. mimNumber 154545 referenceNumber 11 pubmedID 1458688 source Clin. Exp. Immun. 90: 517-521, 1992. authors Garred, P., Thiel, S., Madsen, H. O., Ryder, L. P., Jensenius, J. C., Svejgaard, A. pubmedImages false articleUrl http://link.springer-ny.com/link/service/journals/00335/bibs/9n3p246.html publisherName Springer title The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to chromosome 10. mimNumber 154545 referenceNumber 12 publisherAbbreviation Springer pubmedID 9501312 source Mammalian Genome 9: 246-249, 1998. authors Guo, N., Mogues, T., Weremowicz, S., Morton, C. C., Sastry, K. N. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140673698083500 publisherName Elsevier Science title Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. mimNumber 154545 referenceNumber 13 publisherAbbreviation ES pubmedID 10199352 source Lancet 353: 1049-1053, 1999. authors Hibberd, M. L., Sumiya, M., Summerfield, J. A., Booy, R., Levin, M., {Meningococcal Research Group} pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0019-2805&date=2002&volume=106&issue=3&spage=389 publisherName Blackwell Publishing title Heritability estimates for the constitutional levels of the collectins mannan-binding lectin and lung surfactant protein D. A study of unselected like-sexed mono- and dizygotic twins at the age of 6-9 years. mimNumber 154545 referenceNumber 14 publisherAbbreviation Blackwell pubmedID 12100727 source Immunology 106: 389-394, 2002. authors Husby, S., Herskind, A. M., Jensenius, J. C., Holmskov, U. pubmedImages true publisherUrl http://www.blackwellpublishing.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:1<41::AID-HUMU7>3.0.CO;2-S publisherName John Wiley & Sons, Inc. title Simultaneous genotyping for all three known structural mutations in the human mannose-binding lectin gene. mimNumber 154545 referenceNumber 15 publisherAbbreviation Wiley pubmedID 8990007 source Hum. Mutat. 9: 41-46, 1997. authors Jack, D., Bidwell, J., Turner, M., Wood, N. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=1304173 publisherName HighWire Press title High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. mimNumber 154545 referenceNumber 16 publisherAbbreviation HighWire pubmedID 1304173 source Hum. Molec. Genet. 1: 709-715, 1992. Note: Erratum: Hum. Molec. Genet. 2: 342 only, 1993. authors Lipscombe, R. J., Sumiya, M., Hill, A. V. S., Lau, Y. L., Levinsky, R. J., Summerfield, J. A., Turner, M. W. pubmedImages false publisherUrl http://highwire.stanford.edu title A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. mimNumber 154545 referenceNumber 17 pubmedID 8206524 source Immunogenetics 40: 37-44, 1994. authors Madsen, H. O., Garred, P., Kurtzhals, J. A. L., Lamm, L. U., Ryder, L. P., Thiel, S., Svejgaard, A. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(05)61513-9 publisherName Elsevier Science title Association of mannose-binding-lectin deficiency with severe atherosclerosis. (Letter) mimNumber 154545 referenceNumber 18 publisherAbbreviation ES pubmedID 9752823 source Lancet 352: 959-960, 1998. authors Madsen, H. O., Videm, V., Svejgaard, A., Svennevig, J. L., Garred, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=15472209 publisherName HighWire Press title Mannose-binding lectin gene polymorphisms are associated with gestational diabetes mellitus. mimNumber 154545 referenceNumber 19 publisherAbbreviation HighWire pubmedID 15472209 source J. Clin. Endocr. Metab. 89: 5081-5087, 2004. authors Megia, A., Gallart, L., Fernandez-Real, J.-M., Vendrell, J., Simon, I., Gutierrez, C., Richart, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa033122?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. mimNumber 154545 referenceNumber 20 publisherAbbreviation ATYPON pubmedID 15254284 source New Eng. J. Med. 351: 260-267, 2004. authors Ohlenschlaeger, T., Garred, P., Madsen, H. O., Jacobsen, S. pubmedImages false publisherUrl http://www.atypon.com/ title Deficiency of the sixth component of complement and susceptibility to Neisseria meningitidis infections: studies in 10 families and five isolated cases. mimNumber 154545 referenceNumber 21 pubmedID 3679285 source Immunology 62: 249-253, 1987. authors Orren, A., Potter, P. C., Cooper, R. C., du Toit, E. pubmedImages false title Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. mimNumber 154545 referenceNumber 22 pubmedID 6433145 source Medicine 63: 243-273, 1984. authors Ross, S. C., Densen, P. pubmedImages false title The human mannose-binding protein gene: exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10. mimNumber 154545 referenceNumber 23 pubmedID 2477486 source J. Exp. Med. 170: 1175-1189, 1989. authors Sastry, K., Herman, G. A., Day, L., Deignan, E., Bruns, G., Morton, C. C., Ezekowitz, R. A. B. pubmedImages false title The gene for mannose-binding protein maps to chromosome 10 and is a marker for multiple endocrine neoplasia type 2. mimNumber 154545 referenceNumber 24 pubmedID 1672848 source Cytogenet. Cell Genet. 56: 99-102, 1991. authors Schuffenecker, I., Narod, S. A., Ezekowitz, R. A. B., Sobol, H., Feunteun, J., Lenoir, G. M. pubmedImages false articleUrl http://www.journals.uchicago.edu/cgi-bin/resolve?JID30576PS publisherName University of Chicago Press title Mannose-binding lectin polymorphisms in clinical tuberculosis. mimNumber 154545 referenceNumber 25 publisherAbbreviation UCPJ pubmedID 12934195 source J. Infect. Dis. 188: 777-782, 2003. authors Soborg, C., Madsen, H. O., Andersen, A. B., Lillebaek, T., Kok-Jensen, A., Garred, P. pubmedImages false publisherUrl http://www.journals.uchicago.edu articleUrl http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15749852 publisherName HighWire Press title Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. mimNumber 154545 referenceNumber 26 publisherAbbreviation HighWire pubmedID 15749852 source J. Immun. 174: 3220-3226, 2005. Note: Erratum: J. Immun. 175: 3447 only, 2005. authors Stuart, L. M., Takahashi, K., Shi, L., Savill, J., Ezekowitz, R. A. B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0140-6736(91)93263-9 publisherName Elsevier Science title Molecular basis of opsonic defect in immunodeficient children. mimNumber 154545 referenceNumber 27 publisherAbbreviation ES pubmedID 1675710 source Lancet 337: 1569-1570, 1991. authors Sumiya, M., Super, M., Tabona, P., Levinsky, R. J., Arai, T., Turner, M. W., Summerfield, J. A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(95)90009-8 publisherName Elsevier Science title Mannose binding protein gene mutations associated with unusual and severe infections in adults. mimNumber 154545 referenceNumber 28 publisherAbbreviation ES pubmedID 7707811 source Lancet 345: 886-889, 1995. authors Summerfield, J. A., Ryder, S., Sumiya, M., Thursz, M., Gorchein, A., Monteil, M. A., Turner, M. W. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng0992-50 publisherName Nature Publishing Group title Distinct and overlapping functions of allelic forms of human mannose binding protein. mimNumber 154545 referenceNumber 29 publisherAbbreviation NPG pubmedID 1303250 source Nature Genet. 2: 50-55, 1992. authors Super, M., Gillies, S. D., Foley, S., Sastry, K., Schweinle, J.-E., Silverman, V. J., Ezekowitz, R. A. B. pubmedImages false publisherUrl http://www.nature.com title Structure and evolutionary origin of the gene encoding a human serum mannose-binding protein. mimNumber 154545 referenceNumber 30 pubmedID 2590164 source Biochem. J. 262: 763-771, 1989. authors Taylor, M. E., Brickell, P. M., Craig, R. K., Summerfield, J. A. pubmedImages false articleUrl http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=15994813 publisherName HighWire Press title Mannose binding lectin genotypes influence recovery from hepatitis B virus infection. mimNumber 154545 referenceNumber 31 publisherAbbreviation HighWire pubmedID 15994813 source J. Virol. 79: 9192-9196, 2005. authors Thio, C. L., Mosbruger, T., Astemborski, J., Greer, S., Kirk, G. D., O'Brien, S. J., Thomas, D. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10888598 publisherName HighWire Press title Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians. mimNumber 154545 referenceNumber 32 publisherAbbreviation HighWire pubmedID 10888598 source Hum. Molec. Genet. 9: 1481-1486, 2000. authors Turner, M. W., Dinan, L., Heatley, S., Jack, D. L., Boettcher, B., Lester, S., McCluskey, J., Roberton, D. pubmedImages false publisherUrl http://highwire.stanford.edu title The murine mannose-binding protein genes (Mbl 1 and Mbl 2) localize to chromosomes 14 and 19. mimNumber 154545 referenceNumber 33 pubmedID 7894166 source Mammalian Genome 5: 807-809, 1994. authors White, R. A., Dowler, L. L., Adkison, L. R., Ezekowitz, R. A. B., Sastry, K. N. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15286159 publisherName HighWire Press title Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype. mimNumber 154545 referenceNumber 34 publisherAbbreviation HighWire pubmedID 15286159 source J. Med. Genet. 41: 629-633, 2004. authors Yarden, J., Radojkovic, D., De Boeck, K., Macek, M., Jr., Zemkova, D., Vavrova, V., Vlietinck, R., Cassiman, J.-J., Cuppens, H. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks mgiIDs MGI:96924 mgiHumanDisease true nextGxDx true ncbiReferenceSequences 530393717,171906615 refSeqAccessionIDs NG_008196.1 dermAtlas false hprdIDs 01107 swissProtIDs P11226 zfinIDs ZDB-GENE-000427-2 uniGenes Hs.499674 gtr true cmgGene false ensemblIDs ENSG00000165471,ENST00000373968 umlsIDs C1417054 genbankNucleotideSequences 448994241,23664239,109730114,544339768,448992457,3420793,109730116,3420795,85360966,109730074,71516624,109730073,148139648,23664241,511803995,5911808,357982346,359811822,46854807,23380933,10998278,56159289,5911806,5911795,77702091,448994281,5911793,356581610,357982266,14030459,5911797,34480,357982306,5911791,34486,16973045,5911789,183448400 geneTests true approvedGeneSymbols MBL2 geneIDs 4153 proteinSequences 448994242,1212951,544339769,3420797,448992458,109730115,109730117,85360967,109730075,46854808,126676,23664240,23664242,5911809,578819483,357982347,359811823,578819485,578819487,10998279,578819489,56159290,5911807,119574533,119574534,5911794,448994282,5911792,356581611,14030460,5911798,77702092,357982267,5911796,4557739,5911790,357982307,34487,183448401,64654245 geneticsHomeReferenceIDs gene;;MBL2;;MBL2

entryList

entry status live allelicVariantExists true epochCreated 811926000 geneMap geneSymbols IRS2 sequenceID 9820 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 600797 phenotypeInheritance Autosomal dominant phenotype {Diabetes mellitus, noninsulin-dependent} phenotypeMimNumber 125853 chromosomeLocationStart 110406183 chromosomeSort 260 chromosomeSymbol 13 mimNumber 600797 geneInheritance None confidence P mappingMethod R, REc geneName Insulin receptor substrate 2 mouseMgiID MGI:109334 mouseGeneSymbol Irs2 computedCytoLocation 13q34 cytoLocation 13q34 transcript uc001vqv.3 chromosomeLocationEnd 110438913 chromosome 13 contributors Ada Hamosh - updated : 6/10/2008 Ada Hamosh - updated : 8/20/2007 Marla J. F. O'Neill - updated : 4/17/2007 Marla J. F. O'Neill - updated : 7/8/2005 John A. Phillips, III - updated : 6/28/2005 Marla J. F. O'Neill - updated : 4/11/2005 Marla J. F. O'Neill - updated : 12/2/2004 Cassandra L. Kniffin - updated : 12/4/2003 Victor A. McKusick - updated : 6/10/2003 Dawn Watkins-Chow - updated : 6/13/2002 John A. Phillips, III - updated : 2/14/2002 Joanna S. Amberger - updated : 2/5/2001 George E. Tiller - updated : 1/18/2001 Ada Hamosh - updated : 9/19/2000 Stylianos E. Antonarakis - updated : 9/11/2000 Patti M. Sherman - updated : 6/22/2000 Victor A. McKusick - updated : 8/30/1999 Stylianos E. Antonarakis - updated : 7/12/1999 Clair A. Francomano - updated : 5/7/1998 clinicalSynopsisExists false mimNumber 600797 allelicVariantList allelicVariant status live name DIABETES, TYPE II, SUSCEPTIBILITY TO dbSnps rs1805097 text {10:Mammarella et al. (2000)} genotyped 193 Italian patients with type II diabetes ({125853}) and 206 control subjects for the IRS2 gly1057-to-asp (G1057D) polymorphism. In the absence of obesity, the risk of type II diabetes decreased according to the dosage of the D1057 allele (GD genotype odds ratio 0.46, 95% CI 0.25-0.86; DD 0.18, CI 0.04-0.68; P for trend = 0.0012). Conversely, the interaction between obesity and genotype increased the risk of type II diabetes according to the dosage of the D1057 allele (GD 2.50, CI 1.11-5.65; DD 5.74, CI 1.11-29.78; P for trend = 0.0047). Among controls, fasting C-peptide levels were inversely related to the dosage of the D1057 allele (P = 0.020). The authors suggested that carriers of the D1057 allele may have higher insulin sensitivity and that this allele may have a protective effect. Conversely, among obese patients there was a parallel increase in fasting plasma glucose (P = 0.037) and fasting C-peptide according to the dosage of the D1057 allele, suggesting that higher insulin resistance and relative beta-cell failure contributed to the increased risk of type II diabetes in obese carriers of this allele. The authors concluded that there is evidence for a strong association between type II diabetes and the G1057D common genetic variant of IRS2, which appears to be protective against type II diabetes in a codominant fashion. {5:Fritsche et al. (2001)} tested the hypothesis that an extreme challenge of the beta cell might reveal subtle abnormalities in carriers of this polymorphism undetected by conventional insulin secretion tests. Neither beta-cell function indices from an oral glucose tolerance test nor secretory response during a hyperglycemic clamp differed measurably between carriers and controls. The authors concluded that the G1057D polymorphism in IRS2 is not associated with beta-cell dysfunction. The normal maximal insulin secretory response makes it unlikely that this common polymorphism results in abnormal beta-cell development. mutations IRS2, GLY1057ASP number 1 clinvarAccessions RCV000009368;;1 status live name DIABETES, TYPE II, SUSCEPTIBILITY TO dbSnps rs137852740 text In a Danish individual with type II diabetes ({125853}), {1:Almind et al. (1999)} found a conservative amino acid change of leucine to valine at codon 647 (L647V) of the IRS2 gene. An association study showed that the variant was present in 3 of 413 diabetic patients and absent in 280 glucose-tolerant control subjects. Using the yeast 2-hybrid system, the authors demonstrated that the L647V variant does not affect the interaction between the IRS2 KRLB (kinase regulatory loop-binding) domain and the insulin receptor ({147670}) and p85-alpha of phosphatidylinositol 3-kinase ({171833}), respectively. {21:Wang et al. (2001)} identified the IRS2 L647V variant in a Finnish patient with late-onset type II diabetes. The L647V substitution arises from a C-to-G transversion at nucleotide 1939. mutations IRS2, LEU647VAL number 2 clinvarAccessions RCV000009369;;1 prefix * titles preferredTitle INSULIN RECEPTOR SUBSTRATE 2; IRS2 textSectionList textSection textSectionTitle Cloning textSectionContent The protein IRS1 ({147545}) acts as an interface between signaling proteins with Src homology-2 domains (SH2 proteins) and the receptors for insulin (INS; {176730}), IGF2 ({147470}), growth hormone (GH1; {139250}), several interleukins (IL4, {147780}; IL9, {146931}; IL13, {147683}), and other cytokines. It regulates gene expression and stimulates mitogenesis and appears to mediate insulin/IGF1-stimulated glucose transport. Thus, the finding that the homozygous Irs1 knockout mouse survives with only mild resistance to hypertension was surprising. This dilemma was provisionally resolved by the discovery by {14:Sun et al. (1995)} of a second IRS signaling protein in mouse. They purified and cloned a likely candidate from mouse myeloid progenitor cells and, because of its resemblance to IRS1, they designated it IRS2. Alignment of the sequences of IRS2 and IRS1 demonstrated a highly conserved N terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding (PTB) domain, and a poorly conserved C terminus containing several tyrosine phosphorylation motifs. IRS2 is expressed in many cells, including tissues from the homozygous IRS1 knockout mouse. {14:Sun et al. (1995)} suggested that IRS2 may be essential for signaling by several receptor systems. {11:Ogihara et al. (1997)} screened a human genomic library with a mouse Irs2 cDNA. They isolated a cDNA encoding a full-length human IRS2 protein. Using immunoprecipitation studies, {11:Ogihara et al. (1997)} showed that recombinant IRS2 protein expressed in a baculovirus system can form a complex with 14-3-3 protein (YWHA). They identified a putative 14-3-3 protein-binding site within the PTB domain of IRS2. textSectionName cloning textSectionTitle Mapping textSectionContent The International Radiation Hybrid Mapping Consortium mapped the IRS2 gene to chromosome 13 ({TMAP WI-11813}). textSectionName mapping textSectionTitle Molecular Genetics textSectionContent {10:Mammarella et al. (2000)} genotyped 193 Italian patients with type II diabetes ({125853}) and 206 control subjects for the IRS2 G1057D polymorphism ({600797.0001}). They found evidence for a strong association between type II diabetes and the polymorphism, which appears to be protective against type II diabetes in a codominant fashion. {8:Lautier et al. (2003)} studied a Caucasian population of obese women with class II or class III obesity. These data indicated that IRS2 is an influential gene in severe obesity and glucose intolerance in this population. Furthermore, gene-based haplotypes of IRS2 revealed heterogeneity in the behavior of the gly1057-to-asp mutation ({600797.0001}) in relation to insulin resistance. The study was performed in the south of France, where morbid obesity in females was said to display the highest prevalence rate in the country. Findings indicated that IRS2 is a potential regulator of glucose homeostasis and suggested that IRS2 be added to other candidate loci for obesity. The study provided evidence for heterogeneity in the potential causative role of the gly1057-to-asp mutation, since haplotypes containing this mutation were associated with both normal and obese phenotypes and displayed variable effects on insulin resistance. {4:D'Alfonso et al. (2003)} investigated the significance of the gly1057-to-asp ({600797.0001}) and leu647-to-val ({600797.0002}) IRS2 polymorphisms in 2 Italian cohorts comprising 186 glucose-tolerant subjects and 240 subjects with type II diabetes from the Lazio region (representative of central Italy), and 123 glucose-tolerant subjects from the Sicily region (representative of southern Italy). They concluded that these variants did not appear to affect insulin secretion and insulin sensitivity or to cause major defects in the function of IRS2. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {23:Withers et al. (1998)} demonstrated that homozygous absence of the Irs2 gene results in type II diabetes in mice. Heterozygous and wildtype animals were unaffected. The authors demonstrated profound insulin resistance in both skeletal muscle and liver in the homozygous Irs2 -/- mice. Male mice lacking the Irs2 locus showed polydipsia and polyuria without ketosis and died from dehydration and hyperosmolar coma. A similar disease progression was observed in female mice, with the exception that the females rarely died. The authors concluded that dysfunction of IRS2 may contribute to the pathophysiology of human type II diabetes. {2:Bohni et al. (1999)} showed that chico, a Drosophila homolog of the vertebrate IRS gene family, plays an essential role in the control of cell size and growth. Animals mutant for chico were less than half the size of wildtype flies, owing to fewer and smaller cells. In mosaic animals, chico homozygous cells grew slower than their heterozygous sibs, showed an autonomous reduction in cell size, and formed organs of reduced size. Although chico flies were smaller, they showed an almost 2-fold increase in lipid levels. As indicated, insulin receptor substrates (IRS proteins) mediate the pleiotropic effects of insulin and insulin-like growth factor-1 (IGF1; {147440}), including regulation of glucose homeostasis and cell growth and survival. {22:Withers et al. (1999)} intercrossed mice heterozygous for 2 null alleles, Irs1 +/- and Irs2 +/-, and investigated growth and glucose metabolism in mice with viable genotypes. The experiments showed that Irs1 and Irs2 are critical for embryonic and postnatal growth, with Irs1 having the predominant role. By contrast, both Irs1 and Irs2 function in peripheral carbohydrate metabolism, but Irs2 has the major role in beta-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf1 receptor in beta cells, {22:Withers et al. (1999)} intercrossed mice heterozygous for null alleles of Igf1r ({147370}) and Irs2. The results showed that Igf1 receptors promote beta-cell development and survival through the Irs2 signaling pathway. Thus, Irs2 integrates the effects of insulin in peripheral target tissues with Igf1 in pancreatic beta cells. By studying lipodystrophic (see SREBP1; {184756}) and obese (ob/ob; see {164160}) mice, {13:Shimomura et al. (2000)} showed that chronic hyperinsulinemia downregulates the mRNA for IRS2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS2 deficiency, insulin continues to stimulate production of SREBP1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice. {3:Burks et al. (2000)} demonstrated that the deletion of IRS2, a component of the IGF1 signaling cascade, causes female infertility. Mice lacking IRS2 ({23:Withers et al., 1998}) have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin, and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS2 have increased food intake and obesity despite elevated levels of leptin (LEPR; {601007}). {3:Burks et al. (2000)} concluded that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signaling pathways in the regulation of fertility, metabolism, and longevity in C. elegans and Drosophila, {3:Burks et al. (2000)} identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis. Using gene targeting, {7:Kubota et al. (2000)} generated Irs2-deficient mice that develop diabetes because of inadequate beta-cell proliferation combined with insulin resistance in the liver. They concluded that IRS2 plays a crucial role in the regulation of beta-cell mass. {19:Tobe et al. (2001)} observed that Irs2-deficient mice ({7:Kubota et al. (2000)}) showed increased adiposity with increased serum leptin level, suggesting leptin resistance before the mice developed diabetes. Using oligonucleotide microarray and Northern blot analyses to analyze gene expression, {19:Tobe et al. (2001)} detected increased expression of SREBP1, a downstream target of insulin, in Irs2-deficient mouse liver. Using high-dose leptin administration, they provided evidence that leptin resistance in Irs2-deficient mice is causally related to SREBP1 gene induction. The authors concluded that Irs2 gene disruption results in leptin resistance, causing SREBP1 gene induction, obesity, fatty liver, and diabetes. {6:Hennige et al. (2003)} generated transgenic mice expressing Irs2 at a low or high level in pancreatic beta cells under the control of the rat insulin II promoter. Whereas Irs2-null mice developed diabetes at 4 to 6 weeks and died at about 10 weeks, mice with the low level of Irs2 expression survived for 24 weeks with slow progression toward diabetes, and mice with the high level of Irs2 expression survived up to 15 months without development of hyperglycemia or diabetes, revealing a dosage effect for beta-cell Irs2 expression on glucose homeostasis. Irs2 expression also promoted beta-cell growth and development, upregulated beta-cell gene expression, and inhibited caspase-mediated apoptosis of beta cells. Upregulation of Irs2 promoted glucose tolerance in old mice and prevented diabetes in Irs2-null mice and in obese mice. {6:Hennige et al. (2003)} suggested that the Irs2 signaling cascade may be a 'master regulator' of beta-cell function. {9:Lin et al. (2004)} generated transgenic mice with knockout of Irs2 in the hypothalamus and pancreas. The mice developed diabetes that resolved between 6 and 10 months of age, when functional beta cells expressing Irs2 repopulated the pancreas. {9:Lin et al. (2004)} concluded that Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice. {17:Taniguchi et al. (2005)} used short hairpin RNAs (shRNAs) to knock down Irs1, Irs2, or both, by 70 to 80% in livers of wildtype mice. Knockdown of Irs1 resulted in an upregulation of gluconeogenic enzymes, a decrease in glucokinase (GCK; {138079}) expression, and a trend toward increased blood glucose, whereas knockdown of Irs2 resulted in the upregulation of lipogenic enzymes and increased hepatic lipid accumulation. Concomitant injection of Irs1 and Irs2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. {17:Taniguchi et al. (2005)} concluded that hepatic IRS1 and IRS2 have complementary roles in the control of hepatic metabolism, involving glucose homeostasis and lipid metabolism, respectively. In mouse models of type II diabetes, either Irs2 -/- or Lepr -/- (db/db), {20:Uchida et al. (2005)} observed progressive accumulation of p27 (CDKN1B; {600778}) in the nucleus of pancreatic beta cells. Deletion of Cdkn1b ameliorated hyperglycemia by increasing islet mass and maintaining compensatory hyperinsulinemia, effects which the authors attributed predominantly to stimulation of pancreatic beta-cell proliferation. {20:Uchida et al. (2005)} concluded that p27 contributes to beta-cell failure in the development of type II diabetes in Irs2 -/- and db/db mice. {18:Terauchi et al. (2007)} generated mice with haploinsufficiency of beta cell-specific Gck and observed that on a high-fat diet, Gck +/- mice had decreased beta cell replication and insufficient beta cell hyperplasia compared to wildtype mice despite a similar degree of insulin resistance. On a high-fat diet, Gck +/- mouse islets showed decreased Irs2 expression compared with wildtype islets. Overexpression of Irs2 in beta cells of Gck +/- mice partially prevented diabetes by increasing beta cell mass. {18:Terauchi et al. (2007)} suggested that both GCK and IRS2 are critical for beta cell hyperplasia to occur in response to high-fat diet-induced insulin resistance. {15:Taguchi et al. (2007)} showed that, in mice, less Irs2 signaling throughout the body or only in brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 (SOD2; {147460}) concentrations in the hypothalamus. Thus, {15:Taguchi et al. (2007)} concluded that less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice. {12:Selman et al. (2008)} reported that, using the same mouse model as that used by {15:Taguchi et al. (2007)}, they found no evidence for life span extension and suggested that the findings of {15:Taguchi et al. (2007)} were due to atypical life span profiles in their study animals. In their response to {12:Selman et al. (2008)}, {16:Taguchi and White (2008)} stated that the difference in outcomes in the 2 labs might reflect the effects of diet, breeding strategies, and genetic background on insulin-like signaling cascades. textSectionName animalModel geneMapExists true editHistory carol : 02/26/2013 terry : 11/27/2012 terry : 9/11/2009 joanna : 9/4/2009 joanna : 6/5/2009 joanna : 2/2/2009 alopez : 6/11/2008 terry : 6/10/2008 alopez : 8/28/2007 terry : 8/20/2007 wwang : 4/17/2007 carol : 3/15/2007 wwang : 7/20/2005 wwang : 7/15/2005 terry : 7/8/2005 alopez : 6/28/2005 terry : 4/11/2005 carol : 12/2/2004 carol : 12/8/2003 ckniffin : 12/4/2003 cwells : 6/11/2003 terry : 6/10/2003 alopez : 12/9/2002 terry : 12/6/2002 cwells : 6/13/2002 alopez : 2/14/2002 joanna : 2/6/2001 joanna : 2/5/2001 carol : 2/5/2001 mcapotos : 1/29/2001 mcapotos : 1/19/2001 mcapotos : 1/18/2001 alopez : 9/20/2000 terry : 9/19/2000 mgross : 9/11/2000 mcapotos : 6/23/2000 psherman : 6/22/2000 alopez : 8/31/1999 terry : 8/30/1999 mgross : 7/12/1999 dkim : 12/10/1998 dholmes : 5/7/1998 dholmes : 5/7/1998 mark : 9/24/1995 dateCreated Sun, 24 Sep 1995 03:00:00 EDT creationDate Victor A. McKusick : 9/24/1995 epochUpdated 1361865600 dateUpdated Tue, 26 Feb 2013 03:00:00 EST referenceList reference articleUrl http://link.springer-ny.com/link/service/journals/00125/bibs/9042010/90421244.htm publisherName Springer title Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity. mimNumber 600797 referenceNumber 1 publisherAbbreviation Springer pubmedID 10525667 source Diabetologia 42: 1244-1249, 1999. authors Almind, K., Frederiksen, S. K., Bernal, D., Hansen, T., Ambye, L., Urhammer, S., Ekstrom, C. T., Berglund, L., Reneland, R., Lithell, H., White, M. F., Van Obberghen, E., Pedersen, O. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80799-0 publisherName Elsevier Science title Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. mimNumber 600797 referenceNumber 2 publisherAbbreviation ES pubmedID 10399915 source Cell 97: 865-875, 1999. authors Bohni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B. F., Beckingham, K., Hafen, E. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/35030105 publisherName Nature Publishing Group title IRS-2 pathways integrate female reproduction and energy homeostasis. mimNumber 600797 referenceNumber 3 publisherAbbreviation NPG pubmedID 11014193 source Nature 407: 377-382, 2000. authors Burks, D. J., Font de Mora, J., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., White, M. F. pubmedImages false publisherUrl http://www.nature.com articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=12519871 publisherName HighWire Press title Polymorphisms of the insulin receptor substrate-2 in patients with type 2 diabetes. mimNumber 600797 referenceNumber 4 publisherAbbreviation HighWire pubmedID 12519871 source J. Clin. Endocr. Metab. 88: 317-322, 2003. authors D'Alfonso, R., Marini, M. A., Frittitta, L., Sorge, R., Frontoni, S., Porzio, O., Mariani, L. M., Lauro, D., Gambardella, S., Trischitta, V., Federici, M., Lauro, R., Sesti, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11600548 publisherName HighWire Press title The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion. mimNumber 600797 referenceNumber 5 publisherAbbreviation HighWire pubmedID 11600548 source J. Clin. Endocr. Metab. 86: 4822-4825, 2001. authors Fritsche, A., Madaus, A., Renn, W., Tschritter, O., Teigeler, A., Weisser, M., Maerker, E., Machicao, F., Haring, H., Stumvoll, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI18581 publisherName Journal of Clinical Investigation title Upregulation of insulin receptor substrate-2 in pancreatic beta-cells prevents diabetes. mimNumber 600797 referenceNumber 6 publisherAbbreviation JCI pubmedID 14617753 source J. Clin. Invest. 112: 1521-1532, 2003. authors Hennige, A. M., Burks, D. J., Ozcan, U., Kulkarni, R. N., Ye, J., Park, S., Schubert, M., Fisher, T. L., Dow, M. A., Leshan, R., Zakaria, M., Mossa-Basha, M., White, M. F. pubmedImages true publisherUrl http://www.jci.org articleUrl http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=11078455 publisherName HighWire Press title Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. mimNumber 600797 referenceNumber 7 publisherAbbreviation HighWire pubmedID 11078455 source Diabetes 49: 1880-1889, 2000. authors Kubota, N., Tobe, K., Terauchi, Y., Eto, K., Yamauchi, T., Suzuki, R., Tsubamoto, Y., Komeda, K., Nakano, R., Miki, H., Satoh, S., Sekihara, H., Sciacchitano, S., Lesniak, M., Aizawa, S., Nagai, R., Kimura, S., Akanuma, Y., Taylor, S. I., Kadowaki, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1007/s00439-003-0935-3 publisherName Springer title Complex haplotypes of IRS2 gene are associated with severe obesity and reveal heterogeneity in the effect of gly1057asp mutation. mimNumber 600797 referenceNumber 8 publisherAbbreviation Springer pubmedID 12687350 source Hum. Genet. 113: 34-43, 2003. authors Lautier, C., Ait El Mkadem, S., Renard, E., Brun, J. F., Gris, J. C., Bringer, J., Grigorescu, F. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1172/JCI22217 publisherName Journal of Clinical Investigation title Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. mimNumber 600797 referenceNumber 9 publisherAbbreviation JCI pubmedID 15467829 source J. Clin. Invest. 114: 908-916, 2004. authors Lin, X., Taguchi, A., Park, S., Kushner, J. A., Li, F., Li, Y., White, M. F. pubmedImages true publisherUrl http://www.jci.org articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11030756 publisherName HighWire Press title Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. mimNumber 600797 referenceNumber 10 publisherAbbreviation HighWire pubmedID 11030756 source Hum. Molec. Genet. 9: 2517-2521, 2000. authors Mammarella, S., Romano, F., Di Valerio, A., Creati, B., Esposito, D. L., Palmirotta, R., Capani, F., Vitullo, P., Volpe, G., Battista, P., Della Loggia, F., Mariani-Costantini, R., Cama, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9312143 publisherName HighWire Press title 14-3-3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain. mimNumber 600797 referenceNumber 11 publisherAbbreviation HighWire pubmedID 9312143 source J. Biol. Chem. 272: 25267-25274, 1997. authors Ogihara, T., Isobe, T., Ichimura, T., Taoka, M., Funaki, M., Sakoda, H., Onishi, Y., Inukai, K., Anai, M., Fukushima, Y., Kikuchi, M., Yazaki, Y., Oka, Y., Asano, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=18497277 publisherName HighWire Press title Comment on 'Brain IRS2 signaling coordinates life span and nutrient homeostasis' mimNumber 600797 referenceNumber 12 publisherAbbreviation HighWire pubmedID 18497277 source Science 320: 1012 only, 2008. authors Selman, C., Lingard, S., Gems, D., Partridge, L., Withers, D. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(05)00010-9 publisherName Elsevier Science title Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. mimNumber 600797 referenceNumber 13 publisherAbbreviation ES pubmedID 10949029 source Molec. Cell 6: 77-86, 2000. authors Shimomura, I., Matsuda, M., Hammer, R. E., Bashmakov, Y., Brown, M. S., Goldstein, J. L. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/377173a0 publisherName Nature Publishing Group title Role of IRS-2 in insulin and cytokine signalling. mimNumber 600797 referenceNumber 14 publisherAbbreviation NPG pubmedID 7675087 source Nature 377: 173-177, 1995. authors Sun, X. J., Wang, L.-M., Zhang, Y., Yenush, L., Myers, M. G., Jr., Glasheen, E., Lane, W. S., Pierce, J. H., White, M. F. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=17641201 publisherName HighWire Press title Brain IRS2 signaling coordinates life span and nutrient homeostasis. mimNumber 600797 referenceNumber 15 publisherAbbreviation HighWire pubmedID 17641201 source Science 317: 369-372, 2007. authors Taguchi, A., Wartschow, L. M., White, M. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=short&pmid=18497278 publisherName HighWire Press title Response to comment on 'Brain IRS2 signaling coordinates life span and nutrient homeostasis' mimNumber 600797 referenceNumber 16 publisherAbbreviation HighWire pubmedID 18497278 source Science 320: 1012 only, 2008. authors Taguchi, A., White, M. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI23187 publisherName Journal of Clinical Investigation title Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. mimNumber 600797 referenceNumber 17 publisherAbbreviation JCI pubmedID 15711641 source J. Clin. Invest. 115: 718-727, 2005. Note: Erratum: J. Clin. Invest. 115: 1388 only, 2005. authors Taniguchi, C. M., Ueki, K., Kahn, C. R. pubmedImages true publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1172/JCI17645 publisherName Journal of Clinical Investigation title Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. mimNumber 600797 referenceNumber 18 publisherAbbreviation JCI pubmedID 17200721 source J. Clin. Invest. 117: 246-257, 2007. authors Terauchi, Y., Takamoto, I., Kubota, N., Matsui, J., Suzuki, R., Komeda, K., Hara, A., Toyoda, Y., Miwa, I., Aizawa, S., Tsutsumi, S., Tsubamoto, Y., Hashimoto, S., Eto, K., Nakamura, A., Noda, M., Tobe, K., Aburatani, H., Nagai, R., Kadowaki, T. pubmedImages true publisherUrl http://www.jci.org articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11546755 publisherName HighWire Press title Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2 -/- mouse liver. mimNumber 600797 referenceNumber 19 publisherAbbreviation HighWire pubmedID 11546755 source J. Biol. Chem. 276: 38337-38340, 2001. authors Tobe, K., Suzuki, R., Aoyama, M., Yamauchi, T., Kamon, J., Kubota, N., Terauchi, Y., Matsui, J., Akanuma, Y., Kimura, S., Tanaka, J., Abe, M., Ohsumi, J., Nagai, R., Kadowaki, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/nm1187 publisherName Nature Publishing Group title Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. mimNumber 600797 referenceNumber 20 publisherAbbreviation NPG pubmedID 15685168 source Nature Med. 11: 175-182, 2005. authors Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K. I., White, M. F., Kasuga, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=11473060 publisherName HighWire Press title New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes. mimNumber 600797 referenceNumber 21 publisherAbbreviation HighWire pubmedID 11473060 source Diabetes 50: 1949-1951, 2001. authors Wang, H., Rissanen, J., Miettinen, R., Karkkainen, P., Kekalainen, P., Kuusisto, J., Mykkanen, L., Karhapaa, P., Laakso, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/12631 publisherName Nature Publishing Group title Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. mimNumber 600797 referenceNumber 22 publisherAbbreviation NPG pubmedID 10471495 source Nature Genet. 23: 32-40, 1999. authors Withers, D. J., Burks, D. J., Towery, H. H., Altamuro, S. L., Flint, C. L., White, M. F. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/36116 publisherName Nature Publishing Group title Disruption of IRS-2 causes type 2 diabetes in mice. mimNumber 600797 referenceNumber 23 publisherAbbreviation NPG pubmedID 9495343 source Nature 391: 900-902, 1998. authors Withers, D. J., Gutierrez, J. S., Towery, H., Burks, D. J., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., Bonner-Weir, S., White, M. F. pubmedImages false publisherUrl http://www.nature.com externalLinks mgiIDs MGI:109334 mgiHumanDisease false ncbiReferenceSequences 38683859 refSeqAccessionIDs NG_008154.1 dermAtlas false hprdIDs 02878 swissProtIDs Q9Y4H2 zfinIDs ZDB-GENE-081104-462 uniGenes Hs.442344 gtr true cmgGene false ensemblIDs ENSG00000185950,ENST00000375856 umlsIDs C1334141 genbankNucleotideSequences 12247738,14537853,12247739,15706445,18652856,4511968,24778780,27503652,2809058,39645334,5882162,27445545,15077067,14329908,148165158,148165159,6841245,511796667,19684022,511796668,14537856,83405574 geneTests false approvedGeneSymbols IRS2 geneIDs 8660 proteinSequences 14537854,18652857,4511969,12247740,6841246,62298062,2809059,5882163,15077068,38683860,14537857 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 831625200 geneMap geneSymbols CAV3, LGMD1C, LQT9 sequenceID 2478 phenotypeMapList phenotypeMap phenotypeMimNumber 192600 mimNumber 601253 phenotypeInheritance Autosomal dominant phenotypicSeriesMimNumber 192600 phenotypeMappingKey 3 phenotype Cardiomyopathy, familial hypertrophic phenotypeMappingKey 3 mimNumber 601253 phenotypeInheritance Autosomal dominant phenotype Creatine phosphokinase, elevated serum phenotypeMimNumber 123320 phenotypeMimNumber 611818 mimNumber 601253 phenotypeInheritance None phenotypicSeriesMimNumber 192500 phenotypeMappingKey 3 phenotype Long QT syndrome 9 phenotypeMimNumber 607801 mimNumber 601253 phenotypeInheritance Autosomal recessive; Autosomal dominant phenotypicSeriesMimNumber 159000 phenotypeMappingKey 3 phenotype Muscular dystrophy, limb-girdle, type IC phenotypeMappingKey 3 mimNumber 601253 phenotypeInheritance Autosomal dominant phenotype Myopathy, distal, Tateyama type phenotypeMimNumber 614321 phenotypeMappingKey 3 mimNumber 601253 phenotypeInheritance Autosomal dominant phenotype Rippling muscle disease phenotypeMimNumber 606072 chromosomeLocationStart 8775485 chromosomeSort 24 chromosomeSymbol 3 mimNumber 601253 geneInheritance None confidence C mappingMethod A, REc geneName Caveolin-3 comments within 7-10kb of OXTR mouseMgiID MGI:107570 mouseGeneSymbol Cav3 computedCytoLocation 3p25.3 cytoLocation 3p25 transcript uc003brb.3 chromosomeLocationEnd 8788450 chromosome 3 contributors Patricia A. Hartz - updated : 4/10/2013 Cassandra L. Kniffin - updated : 11/1/2011 George E. Tiller - updated : 10/28/2008 Marla J. F. O'Neill - updated : 2/12/2008 Cassandra L. Kniffin - updated : 2/5/2007 Cassandra L. Kniffin - updated : 12/7/2006 George E. Tiller - updated : 2/17/2006 George E. Tiller - updated : 1/31/2006 Patricia A. Hartz - updated : 12/7/2005 Cassandra L. Kniffin - updated : 4/27/2005 Cassandra L. Kniffin - updated : 2/17/2005 Victor A. McKusick - updated : 2/4/2005 Victor A. McKusick - updated : 10/6/2004 Cassandra L. Kniffin - updated : 8/30/2004 Cassandra L. Kniffin - updated : 2/3/2004 Cassandra L. Kniffin - updated : 1/20/2004 Cassandra L. Kniffin - updated : 6/6/2003 Cassandra L. Kniffin - reorganized : 5/22/2003 Cassandra L. Kniffin - updated : 5/8/2003 Cassandra L. Kniffin - updated : 12/30/2002 George E. Tiller - updated : 1/23/2002 Ada Hamosh - updated : 6/27/2001 George E. Tiller - updated : 4/13/2001 George E. Tiller - updated : 3/5/2001 George E. Tiller - updated : 12/14/2000 Victor A. McKusick - updated : 9/26/2000 Victor A. McKusick - updated : 10/26/1999 Victor A. McKusick - updated : 3/12/1999 Victor A. McKusick - updated : 5/22/1998 Victor A. McKusick - updated : 3/31/1998 clinicalSynopsisExists false mimNumber 601253 allelicVariantList allelicVariant status live name MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C dbSnps rs116840805 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation PRO104LEU. In 4 members over 2 generations of an Italian family with limb-girdle muscular dystrophy type 1C ({607801}), {27:Minetti et al. (1998)} identified a heterozygous 311C-to-T transition in the CAV3 gene, resulting in a pro104-to-leu (P104L) substitution. {12:Galbiati et al. (1999)} stated that P104 resides in the membrane-spanning domain of CAV3. They found that rat Cav3 with the P104L mutation was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. In family A with rippling muscle disease ({606072}) described by {32:Ricker et al. (1989)}, {2:Betz et al. (2001)} identified the P105L mutation. Affected family members had no evidence of limb-girdle muscular dystrophy type 1C. mutations CAV3, PRO105LEU number 1 alternativeNames RIPPLING MUSCLE DISEASE 2, INCLUDED clinvarAccessions RCV000008766;;1;;;RCV000008765;;1;;;RCV000024379;;0 status live name MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C dbSnps rs116840800,rs199476331 text {27:Minetti et al. (1998)} demonstrated that 4 affected members in 3 generations of an Italian family with autosomal dominant limb-girdle muscular dystrophy type 1C ({607801}) had a 9-bp deletion beginning at nucleotide 186 of the CAV3 gene, which resulted in the loss of 3 amino acids (residues 63-65) without changing the open reading frame. {12:Galbiati et al. (1999)} stated that the residues lost in this deletion (TFT) reside within the caveolin scaffolding domain. They found that rat Cav3 with the TFT deletion was excluded from caveolae-enriched membranes, accumulated in the Golgi apparatus, and formed oligomers of much larger size than wildtype Cav3. Mutant Cav3 behaved in a dominant-negative fashion, causing retention of wildtype Cav3 in the Golgi. mutations CAV3, 9-BP DEL, NT186 number 2 clinvarAccessions RCV000024380;;0;;;RCV000008767;;1 status live name MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, AUTOSOMAL RECESSIVE dbSnps rs72546667 text The numbering of this CAV3 mutation (G56S) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation GLY55SER. Whereas autosomal dominant limb-girdle muscular dystrophy type 1C ({607801}) has been related to heterozygous CAV3 mutations, {25:McNally et al. (1998)} found homozygosity for a gly55-to-ser change (G55S) in 1 of 82 patients with muscular dystrophy screened for mutations in the CAV3 gene. This patient was the only affected member of her family, and developed proximal muscle weakness in the first decade. The mutation was not identified in 200 control chromosomes. Expression of dystrophin, the sarcoglycans, and caveolin-3 was grossly normal in a skeletal muscle biopsy from the patient, and the authors suggested that the G55S change may not alter the intracellular location of the protein, yet may interfere with the normal function of the protein in the membrane. Among 61 Brazilian patients with LGMD, {6:de Paula et al. (2001)} identified 2 patients with a heterozygous G55S mutation. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening of 200 normal Brazilian chromosomes revealed heterozygosity for the G55S change in 4 subjects and for a C71W change ({601253.0004}) in 1 subject. The authors concluded that the G55S and C71W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. The abnormal phenotype in the 2 patients is likely caused by mutation in another LGMD gene. mutations CAV3, GLY56SER number 3 clinvarAccessions RCV000008768;;1;;;RCV000039799;;2;;;RCV000119393;;1 status live name MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C dbSnps rs116840776 text The numbering of this CAV3 mutation (C72W) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation CYS71TRP. In 1 of 82 patients with muscular dystrophy, {25:McNally et al. (1998)} identified a heterozygous C-to-G change in the CAV3 gene, resulting in a cys71-to-trp (C71W) substitution. The patient had progressive proximal muscle weakness beginning in the first decade, but remained ambulatory in the mid-second decade. Her mother and 2 siblings had the identical missense change, but did not have symptoms of muscular dystrophy, suggesting that a single abnormal allele is not sufficient to cause the phenotype and that the likely inheritance is autosomal recessive. The authors were unable to determine the nature of the second allele in the proband. The mutation was not identified in 200 control chromosomes. {24:McNally (1998)} suspected that the phenotype was the result of either loss-of-function mutations or dominant-negative mutations; she doubted that haploinsufficiency leads to the disease. The family was lost to follow-up. Among 100 normal Brazilian control subjects without LGMD, {6:de Paula et al. (2001)} identified heterozygosity for the C71W change in 1 subject. They concluded that C71W is a rare polymorphism that does not cause an abnormal phenotype when present in just one allele. mutations CAV3, CYS72TRP number 4 clinvarAccessions RCV000008769;;1;;;RCV000024381;;0 status live name MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C dbSnps rs116840789,rs121909276 text The numbering of this CAV3 mutation (A46T) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation ALA45THR. In a 4-year-old girl presenting with myalgia and muscle cramps consistent with limb-girdle muscular dystrophy type 1C ({607801}), {18:Herrmann et al. (2000)} identified a heterozygous 136G-to-A change, resulting in an ala46-to-thr substitution. The mutation prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. In 2 unrelated families with rippling muscle disease ({606072}) from Germany, reported by {39:Vorgerd et al. (1999)}, and the first-described RMD family from Norway, reported by {37:Torbergsen (1975)}, {2:Betz et al. (2001)} identified a heterozygous mutation in the CAV3 gene, resulting in an ala45-to-thr substitution (A45T). A muscle biopsy from a patient carrying the mutation showed decreased surface expression of the caveolin-3 protein. {10:Fulizio et al. (2005)} identified the A46T mutation in 4 unrelated patients with decreased caveolin-3 on muscle biopsy. Three patients had myalgia and/or mild proximal muscle weakness, whereas 1 had frank LGMD1C. Three of the patients had a positive family history of muscle-related disorders. The father and 2 paternal uncles of 1 patient with mild muscle weakness were reportedly asymptomatic with elevated serum creatine kinase ({123320}). Skeletal muscle caveolin-3 protein in the 4 probands ranged from less than 5 to 10%. mutations CAV3, ALA46THR number 5 alternativeNames RIPPLING MUSCLE DISEASE 2, INCLUDED;; CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED clinvarAccessions RCV000008772;;1;;;RCV000024382;;0;;;RCV000008774;;1;;;RCV000008773;;1 status live name RIPPLING MUSCLE DISEASE 2 dbSnps rs116840773,rs121909277 text The numbering of this CAV3 mutation (A46V) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation ALA45VAL. In a family with rippling muscle disease ({606072}) described by {32:Ricker et al. (1989)}, {2:Betz et al. (2001)} identified a mutation in the CAV3 gene, resulting in an ala45-to-val (A45V) substitution. mutations CAV3, ALA46VAL number 6 clinvarAccessions RCV000008775;;1;;;RCV000024383;;0 status live name RIPPLING MUSCLE DISEASE 2 dbSnps rs121909278,rs116840778 text The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation ARG26GLN. In kindred B with autosomal dominant rippling muscle disease ({606072}) described by {39:Vorgerd et al. (1999)}, {2:Betz et al. (2001)} identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. In a patient with sporadic rippling muscle disease, {40:Vorgerd et al. (2001)} identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. {40:Vorgerd et al. (2001)} suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. {4:Carbone et al. (2000)} identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; {123320}) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. {4:Carbone et al. (2000)} concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. In a Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; {614321}), {36:Tateyama et al. (2002)} identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin ({603009}) immunoreactivity. {36:Tateyama et al. (2002)} noted the unusual clinical phenotype of the patient. In a 71-year-old woman with limb-girdle muscular dystrophy type 1C ({607801}), {8:Figarella-Branger et al. (2003)} identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. {8:Figarella-Branger et al. (2003}) emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. {15:Gonzalez-Perez et al. (2009)} identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. {15:Gonzalez-Perez et al. (2009)} noted the variable phenotypic features in this family. mutations CAV3, ARG27GLN number 7 alternativeNames CREATINE PHOSPHOKINASE, ELEVATED SERUM, INCLUDED;; MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, INCLUDED;; MYOPATHY, DISTAL, TATEYAMA TYPE, INCLUDED clinvarAccessions RCV000008778;;1;;;RCV000008777;;1;;;RCV000008776;;1;;;RCV000023083;;1 status live name RIPPLING MUSCLE DISEASE 2 dbSnps rs116840782,rs121909279 text The numbering of this CAV3 mutation (D28E) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation ASP27GLU. In 9 affected members of a large German family with autosomal dominant rippling muscle disease ({606072}), {9:Fischer et al. (2003)} identified a heterozygous C-A change in exon 1 of the CAV3 gene, resulting in an asp27-to-glu (D27E) substitution within the N terminus of the protein. The mutation was not detected in 10 unaffected family members or in 200 normal control chromosomes. Five of the 9 patients had additional signs of a distal myopathy with ankle and hand weakness and atrophy. Two other patients had predominantly proximal muscle weakness consistent with limb-girdle muscular dystrophy type 1C ({607801}). The 2 youngest patients showed only isolated signs of rippling muscle disease without muscle weakness or atrophy. Immunohistochemical and Western blot analysis showed a severe reduction of CAV3 protein expression in skeletal muscle from the index patient, supporting a dominant-negative effect of the mutation. The authors commented on the marked intrafamilial clinical variability caused by the mutation. mutations CAV3, ASP28GLU number 8 alternativeNames MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, INCLUDED clinvarAccessions RCV000024386;;0;;;RCV000008770;;1;;;RCV000008771;;1 status live name RIPPLING MUSCLE DISEASE 2 dbSnps rs28936685 text The numbering of this CAV3 mutation (L87P) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation LEU86PRO. In a Colombian patient with severe rippling muscle disease ({606072}), {20:Kubisch et al. (2003)} identified a homozygous 215T-C transition in the CAV3 gene, resulting in a leu86-to-pro substitution (L86P) in the membrane-associated domain of the protein. The patient had muscle stiffness in his legs since the age of 3 years and contractures of the Achilles tendon leading to gait disturbances. At age 20, he had elevated creatine kinase levels, hypertrophic skeletal muscles, and generalized rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin ({603009}). The patient did not have family members available for further study, so it could not be determined if the mutation represented autosomal recessive RMD. {20:Kubisch et al. (2003)} noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies, including RMD and LGMD1C ({607801}), are part of a clinical continuum. mutations CAV3, LEU87PRO number 9 clinvarAccessions RCV000024387;;0;;;RCV000008779;;1 status live name RIPPLING MUSCLE DISEASE 2, AUTOSOMAL RECESSIVE dbSnps rs28936686 text The numbering of this CAV3 mutation (A93T) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation ALA92THR. In an Italian patient with severe rippling muscle disease ({606072}), {20:Kubisch et al. (2003)} identified a homozygous 232G-A transition in the CAV3 gene, resulting in an ala92-to-thr substitution (A92T) in the membrane-associated domain of the protein. The patient had slowly progressive muscle weakness beginning in early adulthood, elevated creatine kinase, and rapid muscle contractions. Muscle biopsy showed almost complete loss of caveolin-3 expression and reduced dysferlin ({603009}). {20:Kubisch et al. (2003)} noted that the patient was more severely clinically affected than those with heterozygous mutations and suggested that caveolinopathies, including RMD and LGMD1C ({607801}), are part of a clinical continuum. {19:Kubisch et al. (2005)} identified homozygosity for the A92T mutation in 2 German sibs with childhood-onset of rippling muscle disease. Both unaffected parents were heterozygous for the mutation. The findings indicated that there is a form of autosomal recessive RMD in which heterozygous carriers do not manifest the disease. Haplotype analysis indicated that the mutation arose independently from the mutation observed in the Italian patient reported by {20:Kubisch et al. (2003)}, suggesting that A92T is a mutation hotspot. mutations CAV3, ALA93THR number 10 clinvarAccessions RCV000008780;;1;;;RCV000024388;;0 status live name CREATINE PHOSPHOKINASE, ELEVATED SERUM dbSnps rs116840802,rs199476335 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation PHE97DEL. {3:Cagliani et al. (2003)} reported a multigenerational Italian family with deletion of nucleotides 328-330 in the CAV3 gene, resulting in deletion of phenylalanine at codon 97. All members with the mutation had elevated serum creatine kinase ({123320}), but there was remarkable intrafamilial variation in other features, including rippling muscle disease ({606072}), proximal limb weakness, distal limb weakness, and a more severe limb-girdle muscular dystrophy ({607801}). Muscle biopsy of 3 affected patients showed myopathic changes and a deficiency of caveolin-3 by immunostaining and Western blot analysis. A heart biopsy in 1 patient showed that caveolin-3 was present at approximately 60% of the normal level. {3:Cagliani et al. (2003)} noted that the findings provided an explanation of why heart involvement is not a feature of caveolinopathies, and suggested that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. mutations CAV3, 3-BP DEL, PHE98DEL number 11 alternativeNames RIPPLING MUSCLE DISEASE 2, INCLUDED;; MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1C, INCLUDED clinvarAccessions RCV000024390;;0;;;RCV000008781;;1;;;RCV000008783;;1;;;RCV000008782;;1 status live name CREATINE PHOSPHOKINASE, ELEVATED SERUM dbSnps rs116840786 text The numbering of this CAV3 mutation (P29L) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation PRO28LEU. In an 18-year-old man and his mother with isolated persistent hyperCKemia ({123320}), {26:Merlini et al. (2002)} identified a heterozygous 83C-T transition in exon 1 of the CAV3 gene, resulting in a pro28-to-leu (P28L) substitution. Muscle biopsy showed partial CAV3 deficiency, but neither patient had any signs or symptoms of myopathy. The mutation was not found in 50 patients with different myopathies or in 100 normal controls. mutations CAV3, PRO29LEU number 12 clinvarAccessions RCV000008784;;1;;;RCV000024389;;0 status live name CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC dbSnps rs116840799,rs121909280 text The numbering of this CAV3 mutation (T64S) is based on the numbering system used by {10:Fulizio et al. (2005)}. Early reports designated this mutation THR63SER. In 2 Japanese brothers with hypertrophic cardiomyopathy ({192600}) whose father had hypertrophic cardiomyopathy and had died suddenly at the age of 41 years, {17:Hayashi et al. (2004)} identified a thr63-to-ser (T63S) mutation in the CAV3 gene. The threonine at codon 63 is evolutionarily conserved in the scaffolding domain of caveolin-3. Two mutations involving codon 63 had been earlier reported, T63P and deletion of 3 amino acids at positions 63-65 ({601253.0002}) in LGMD1C. {17:Hayashi et al. (2004)} stated that the clinical findings of the index patient with the T63S mutation was mild. At the age of 16, he showed marginal concentric left ventricular hypertrophy and his left ventricular end-diastolic pressure was high in catheterization studies. His electrocardiogram showed high voltage. After 9 years' follow-up, left ventricular wall thickness was not changed markedly, but dilatation of the left ventricular and systolic dimension were increased. Similar phenotypes were found in his brother. Both of them as well as their father had no symptoms of skeletal muscle disorder and no elevation of serum creatine kinase, suggesting that they were not affected with LGMD, rippling muscle disease, or hyperCKemia. mutations CAV3, THR64SER number 13 clinvarAccessions RCV000024395;;0;;;RCV000008785;;1 status live name MYOPATHY, DISTAL, TATEYAMA TYPE dbSnps rs1008642 text In a mother and daughter with distal myopathy and absence of caveolin-3 protein (MPDT; {614321}) on skeletal muscle biopsy, {10:Fulizio et al. (2005)} identified a heterozygous 99C-G transversion in exon 1 of the CAV3 gene, resulting in an asn33-to-lys (N33K) substitution in the N-terminal domain of the protein. Ages at onset were 30 and 27 years, respectively. mutations CAV3, ASN33LYS number 14 clinvarAccessions RCV000008786;;1 status live name RIPPLING MUSCLE DISEASE 2 dbSnps rs116840793 text The numbering of this CAV3 mutation (E47K) is based on the numbering system used by {10:Fulizio et al. (2005)}. Other reports designated this mutation GLU46LYS. In a father and son with rippling muscle disease ({606072}), {22:Madrid et al. (2005)} identified a heterozygous 136G-A transition in exon 2 of the CAV3 gene, resulting in a glu46-to-lys (E46K) substitution. Muscle biopsy from the father showed absence of caveolin-3 immunostaining. Unusual features in both these patients included congenital pes equinus deformity and early toe walking, which resolved after orthopedic surgical correction. In addition, the father had nonprogressive mild proximal muscle weakness, and the son demonstrated percussion-induced rapid contractions of the thenar muscles without overt rippling of other muscles. mutations CAV3, GLU47LYS number 15 clinvarAccessions RCV000008787;;1;;;RCV000024416;;0 status live name LONG QT SYNDROME 9 dbSnps rs104893713 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In a 16-year-old white male with nonexertional dyspnea and a QTc of 480 ms (LQT9; {611818}) who was negative for mutations in known LQT genes, {38:Vatta et al. (2006}) identified heterozygosity for a de novo 423C-G transversion in the CAV3 gene, resulting in a ser141-to-arg (S141R) substitution at a conserved residue in the functional C-terminal domain. Consistent with his negative family history and normal screening ECGs among first-degree relatives, genetic testing confirmed that neither parent carried the mutation, which was also not found in more than 1,000 control alleles. Functional studies demonstrated that S141R-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. mutations CAV3, SER141ARG number 16 clinvarAccessions RCV000008788;;1;;;RCV000024432;;0 status live name LONG QT SYNDROME 9, ACQUIRED, SUSCEPTIBILITY TO dbSnps rs104893714 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In a 13-year-old asthmatic girl with long QT syndrome (LQT9; {611818}) who was negative for mutations in known LQT genes, {38:Vatta et al. (2006)} identified heterozygosity for a de novo 290T-G transversion in the CAV3 gene, resulting in a phe97-to-cys (F97C) substitution at a highly conserved residue in the transmembrane domain. The patient presented with shortness of breath and chest pain; ECG showed marked QT prolongation with a QTc of 532 ms, which was present only, but reproducibly, on beta-agonist inhaler therapy for her asthma. The family history was unremarkable, and screening ECGs in all first-degree relatives showed normal QTc. The mutation was not found in either of her parents or in more than 1,000 control alleles. Functional studies demonstrated that F97C-mutant caveolin-3 resulted in a 2- to 3-fold increase in late sodium current compared to wildtype. mutations CAV3, PHE97CYS number 17 clinvarAccessions RCV000024431;;0;;;RCV000008789;;1 status live name LONG QT SYNDROME 9 dbSnps rs72546668 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In 3 unrelated individuals with long QT syndrome (LQT9; {611818}), {38:Vatta et al. (2006)} identified heterozygosity for a 233C-T transition in the CAV3 gene, resulting in a thr78-to-met (T78M) substitution at a highly conserved residue. All 3 patients had a positive family history, but family members declined further genotyping. One patient had biallelic digenic mutations: she was a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, and was found to carry a A913V mutation in the LQT2-associated KCNH2 gene ({152427.0024}) as well as the T78M mutation. The other 2 patients, who were negative for mutations in other known LQTS genes, were an 8-year-old boy with nonexertional syncope and marked sinus bradycardia with a QTc of 433 ms and an asymptomatic 40-year-old male who had a QTc of 456 ms. The T78M mutation was not found in more than 1,000 control alleles. In frozen necropsy tissue from a 2-month-old black female infant who died of sudden infant death syndrome (SIDS; {272120}), {5:Cronk et al. (2007)} identified the T78M mutation in the CAV3 gene. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. mutations CAV3, THR78MET number 18 alternativeNames LONG QT SYNDROME 2/9, DIGENIC, INCLUDED clinvarAccessions RCV000024406;;2;;;RCV000008791;;1;;;RCV000008790;;1;;;RCV000039801;;1;;;RCV000143872;;1 status live name LONG QT SYNDROME 9 dbSnps rs104893715 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In a 36-year-old female who suffered a cardiac arrest while sleeping (LQT9; {611818}), {38:Vatta et al. (2006)} identified heterozygosity for a 253G-A transition in the CAV3 gene, resulting in an ala85-to-thr (A85T) substitution at a conserved residue. The mutation was not found in more than 1,000 control alleles. mutations CAV3, ALA85THR number 19 clinvarAccessions RCV000024430;;0;;;RCV000008792;;1 status live name LONG QT SYNDROME 9 dbSnps rs121909281 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In frozen necropsy tissue from a 6-month-old black male infant who died of sudden infant death syndrome (SIDS; {272120}), {5:Cronk et al. (2007)} identified a 40G-C transversion in the CAV3 gene, resulting in a val14-to-leu (V14L) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. mutations CAV3, VAL14LEU number 20 clinvarAccessions RCV000008793;;1;;;RCV000024433;;0 status live name LONG QT SYNDROME 9 dbSnps rs121909282 text The numbering of this CAV3 mutation is based on the numbering system used by {10:Fulizio et al. (2005)}. In frozen necropsy tissue from an 8-month-old black female infant who died of sudden infant death syndrome (SIDS; {272120}), {5:Cronk et al. (2007)} identified a 236T-G transversion in the CAV3 gene, resulting in a leu79-to-arg (L79R) substitution at a highly conserved residue. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. mutations CAV3, LEU79ARG number 21 clinvarAccessions RCV000024434;;0;;;RCV000008794;;1 prefix * titles alternativeTitles M-CAVEOLIN preferredTitle CAVEOLIN 3; CAV3 textSectionList textSection textSectionTitle Description textSectionContent Caveolin-3 (M-caveolin) is the muscle-specific form of the caveolin protein family, which also includes caveolin-1 (CAV1; {601047}) and caveolin-2 (CAV2; {601048}). Caveolins are the principal protein components of caveolae ('little caves'), 50 to 100 nm invaginations found in most cell types which represent appendages or subcompartments of plasma membranes ({27:Minetti et al., 1998}). Caveolin-3 plays a role in muscle development and physiology. In adult muscle, it is present throughout the T tubule system, but is clustered in subsarcolemmal areas critical for the electrical transmission of the contractile impulse. In the sarcolemma, caveolin-3 belongs to the dystrophin-glycoprotein complex and confers stability to the muscle cell membrane. In addition to these structural roles, caveolin-3 has functional roles in signaling pathways and energy metabolism (review by {14:Gazzerro et al., 2010}). textSectionName description textSectionTitle Cloning textSectionContent To identify other putative members of the G protein-associated caveolin gene family, {35:Tang et al. (1996)} searched existing databases for genomic sequences related to the protein sequence of caveolin-1. They identified a rat sequence that appeared to encode a novel caveolin-like gene and designed oligonucleotide primers with which to amplify purified rat genomic DNA. They designated the new gene caveolin-3 (CAV3). Rat caveolin-3 is approximately 65% identical and 85% similar to rat caveolin-1. The authors noted that a single stretch of amino acids (FEDVIAEP) is identical in caveolin-1, -2, and -3, and may represent a 'caveolin signature sequence' characteristic of this family. {35:Tang et al. (1996)} further characterized the biochemistry, cellular localization, and tissue specificity of caveolin-3. They detected the CAV3 transcript only in rat skeletal muscle, diaphragm, and heart tissues, but noted that CAV3 expression was specific to the endothelial cells surrounding the muscle fibers. Additionally, they observed that a caveolin-3-derived polypeptide conserved in caveolin-1 either suppresses or stimulates the basal GTPase activity of purified heterotrimeric G proteins (see {600239}) in a concentration-dependent manner. {25:McNally et al. (1998)} cloned the CAV3 gene and found that the cDNA encodes an open reading frame of 150 amino acids with 96% homology to the rat and mouse sequences. CAV3 mRNA was expressed exclusively in cardiac and skeletal muscle. {27:Minetti et al. (1998)} stated that caveolin-3 contains a 20-amino acid scaffolding domain (residues 54 to 73) that is critical for homo-oligomerization and for interaction with several caveolin-associated signaling molecules. A 33-amino acid hydrophobic domain (residues 74 to 106) of caveolin-3, which spans the membrane, is thought to form a hairpin loop within the cell membrane, allowing both the amino- and carboxy-terminal domains to face the cytoplasm. Comparison of caveolins-1, -2, and -3 with caveolins-1 and -2 of Caenorhabditis elegans showed that only 12 amino acid residues are invariant between worms and man. {28:Nixon et al. (2005)} noted that CAV3 shares 72% identity with its zebrafish homolog. textSectionName cloning textSectionTitle Gene Structure textSectionContent {25:McNally et al. (1998)} determined that the CAV3 gene contains 2 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent By fluorescence in situ hybridization, {27:Minetti et al. (1998)} and {25:McNally et al. (1998)} mapped the CAV3 gene to chromosome 3p25. To map the CAV3 gene more precisely, {33:Sotgia et al. (1999)} isolated 3 independent BAC clones containing the human CAV3 gene. Using a PCR-based approach, they determined that these clones contained both exons 1 and 2 of the CAV3 gene. In addition, they performed microsatellite marker analysis of these BAC clones, using a panel of 13 markers that are known to map within the 3p25 region. They identified 3 markers within these BAC clones, one of which, D3S18, is a marker for 2 known human diseases, von Hippel-Lindau disease (VHL; {193300}) and 3p- syndrome. Two of the markers were known to map in the vicinity of the 3-prime end of the oxytocin receptor gene (OXTR; {167055}). {33:Sotgia et al. (1999)} showed that these BACs contained all 4 exons of the oxytocin receptor gene, and that the genes encoding CAV3 and OXTR are located approximately 7 to 10 kb apart and are transcribed in opposite orientation. textSectionName mapping textSectionTitle Gene Function textSectionContent {25:McNally et al. (1998)} showed that caveolin-3 copurifies with dystrophin ({300377}) in rat skeletal muscle membrane, suggesting a role in muscular dystrophy. The authors noted, however, that a significant fraction of the caveolin present in the rat skeletal muscle did not copurify with dystrophin, suggesting that caveolin is not associated exclusively with the dystrophin-glycoprotein complex (DGC) in muscle. Dysferlin (DYSF; {603009}) is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited forms of muscular dystrophy designated Miyoshi myopathy (MM; {254130}) and limb-girdle muscular dystrophy type 2B (LGMD2B; {253601}), respectively. {23:Matsuda et al. (2001)} reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae. Abnormal localization of dysferlin was seen in muscles from patients with limb-girdle muscular dystrophy type 1C (LGMD1C; {607801}), including one with a novel missense mutation in CAV3. The 3p- syndrome results from a hemizygous deletion of 3pter-p25 and is characterized by growth retardation, specific craniofacial features (microcephaly, ptosis, micrognathia), mental retardation, and cardiac septal defects ({7:Drumheller et al., 1996}). {33:Sotgia et al. (1999)} suggested that the CAV3 gene may be deleted in 3p- syndrome. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Skeletal Muscle Phenotypes Mutations in the CAV3 gene can cause 4 different skeletal muscle phenotypes, including limb-girdle muscular dystrophy type 1C (LGMD1C; {607801}); rippling muscle disease-2 (RMD2; {606072}); isolated hyperCKemia ({123320}); and distal myopathy (MPDT; {614321}). Many patients show an overlap of these skeletal muscle entities, and some authors have suggested that the caveolinopathies constitute a clinical continuum. Moreover, there are no genotype/phenotype correlations, the same mutation can cause heterogeneous phenotypes, and there is intrafamilial variability. Most of the mutations cause a loss of caveolin-3 in skeletal muscle biopsy (review by {14:Gazzerro et al., 2010}). In 2 families with autosomal dominant limb-girdle muscular dystrophy type 1C, {27:Minetti et al. (1998)} identified 2 heterozygous mutations in the CAV3 gene: a missense mutation in the membrane-spanning region ({601253.0001}) and a microdeletion in the scaffolding domain ({601253.0002}). The mutations altered conserved invariant amino acid residues. {27:Minetti et al. (1998)} predicted that these mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane. Among 82 patients with muscular dystrophy of unknown genetic etiology, {25:McNally et al. (1998)} identified 1 female with a homozygous missense change in the CAV3 gene (G56S; {601253.0003}). A second patient was identified with a heterozygous change on 1 allele (C72W; {601253.0004}). Both mutations fall within a cytoplasmic region of caveolin-3 that had been implicated directly in inhibiting activity of neuronal nitric oxide synthase (NOS1; {163731}). NOS1 is part of the dystrophin-glycoprotein complex, and its association with the muscle membrane is altered in Duchenne muscular dystrophy (DMD; {310200}). Among 100 Brazilian normal control subjects without LGMD, {6:de Paula et al. (2001)} found 4 subjects who were heterozygous for the G55S change and 1 subject who was heterozygous for the C72W change. The authors concluded that the G56S and C72W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. {18:Herrmann et al. (2000)} reported a 4-year-old girl presenting with myalgia and muscle cramps due to a heterozygous substitution in the caveolin-3 gene ({601253.0005}) that prevented the localization of caveolin-3 to the plasma membrane in a dominant-negative fashion. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan (DAG1; {128239}) expression was detected in the caveolin-3-deficient patient. The authors hypothesized common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies and caveolin-3-deficient limb-girdle muscular dystrophy. {4:Carbone et al. (2000)} identified a de novo recurrent sporadic mutation in the CAV3 gene ({601253.0007}) in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; {123320}) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. {4:Carbone et al. (2000)} concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. In 5 families with autosomal dominant rippling muscle disease ({606072}), {2:Betz et al. (2001)} identified 4 missense mutations in the CAV3 gene (see, e.g., {601253.0001}). They found that the same mutations in the CAV3 gene can give rise to rippling muscle disease, sporadic hyperCKemia, and autosomal dominant LGMD1C. {10:Fulizio et al. (2005)} screened 663 patients with various phenotypes of unknown etiology (primarily clinical diagnoses of unclassified limb-girdle muscular dystrophy (LGMD), hyperCKemia, and proximal myopathy), for caveolin-3 protein deficiency, and identified 8 caveolin-deficient patients from 7 families with CAV3 mutations. Four of the patients had the A46T mutations ({601253.0005}). The authors noted the wide phenotypic and histologic variations in patients with the same mutation or from the same families, precluding a clear genotype/phenotype correlation. {10:Fulizio et al. (2005)} estimated that caveolinopathies represent 1% of both unclassified LGMD and other phenotypes, and demonstrated that caveolin-3 protein deficiencies are a highly sensitive and specific marker of primary caveolinopathy. Hypertrophic Cardiomyopathy and Long QT Syndrome {17:Hayashi et al. (2004)} examined the CAV3 gene for mutation in patients with hypertrophic cardiomyopathy (CMH; {192600}) or dilated cardiomyopathy. They found a thr64-to-ser mutation ({601253.0013}) in 2 brothers with hypertrophic cardiomyopathy but not in their mother, who did not show left ventricular hypertrophy. Thus, it was suggested that the mutation had been inherited from their father, but this could not be confirmed since the father, who was also affected with hypertrophic cardiomyopathy, had died suddenly at the age of 41 years. {38:Vatta et al. (2006)} analyzed the CAV3 gene in 905 unrelated patients with long QT syndrome who had previously been tested for mutations in known LQT genes and identified 4 heterozygous missense mutations in 6 patients ({601253.0016}-{601253.0019}, respectively) with LQT9 ({611818}). The mutations were not found in more than 1,000 control alleles. Electrophysiologic analysis of transiently transfected HEK293 cells stably expressing the cardiac sodium channel demonstrated that the mutant caveolin-3 resulted in a 2- to 3-fold increase in the late sodium current compared with wildtype caveolin-3. One patient had biallelic digenic mutations, with a missense mutation in the LQT2 ({613688})-associated KCNH2 gene ({152427}) as well as in the CAV3 gene (see {601253.0018} and {152427.0024}) Sudden Infant Death Syndrome {5:Cronk et al. (2007)} analyzed the CAV3 gene in necropsy tissue from 134 unrelated cases of sudden infant death syndrome (SIDS; {272120}) and identified 3 missense mutations in 3 of 50 black infants ({601253.0018}; {601253.0020}; and {601253.0021}). No mutations were detected in 1 Hispanic or 83 white infants. Voltage-clamp studies demonstrated a gain-of-function phenotype for all 3 CAV3 mutations, with a 5-fold increase in late sodium current compared to controls. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {16:Hagiwara et al. (2000)} developed caveolin-3-deficient mice for use as animal models of caveolinopathy. Caveolin-3 mRNA and its protein were absent in homozygous mutant mice. Muscle degeneration was recognized in soleus muscle at 8 weeks of age and in the diaphragm from 8 to 30 weeks, although there was no difference in growth and movement between wildtype and mutant mice. No apparent muscle degeneration was observed in heterozygous mutant mice, consistent with autosomal recessive transmission of the phenotype. This is in contrast to the dominant-negative acting missense mutations found in human LGMD1C. Duchenne muscular dystrophy patients and mdx mice show elevated levels of caveolin-3 expression in skeletal muscle. To investigate whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of the disorder, {11:Galbiati et al. (2000)} overexpressed wildtype caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3-overexpressing transgenic mice showed a dramatic increase in the number of sarcolemmal muscle cell caveolae; a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and downregulation of dystrophin and beta-dystroglycan protein expression. In addition, the mice showed elevated serum creatine kinase levels, consistent with the myonecrosis observed morphologically. {34:Sunada et al. (2001)} generated transgenic mice expressing the pro105-to-leu mutant caveolin-3 (P105L; {601253.0001}). Mice showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, suggesting a dominant-negative effect of mutant caveolin-3. Caveolin-3 had been shown to interact with neuronal nitric oxide synthase (nNOS; {163731}) and inhibit its catalytic activity ({13:Garcia-Cardena et al., 1997}). {34:Sunada et al. (2001)} found a great increase of nNOS activity in the transgenic skeletal muscle, suggesting a role for nitric oxide synthase in muscle fiber degeneration in caveolin-3 deficiency. {1:Aravamudan et al. (2003)} showed that Cav3-overexpressing transgenic mice had severe cardiac tissue degeneration, fibrosis, and a reduction in cardiac functions. Dystrophin and its associated glycoproteins were downregulated in Cav3 transgenic hearts. In addition, the activity of nitric oxide synthase was downregulated by high levels of caveolin-3 in the heart. Caveolin-3 binds to eNOS (NOS3; {163729}) in cardiac myocytes and nNOS in skeletal myocytes. {30:Ohsawa et al. (2004)} characterized the biochemical and cardiac parameters of P105L mutant mice, a model of LGMD1C. Transgenic mouse hearts demonstrated hypertrophic cardiomyopathy, enhanced basal contractility, decreased left ventricular end diastolic diameter, and loss and cytoplasmic mislocalization of Cav3 protein. Cardiac muscle showed activation of eNOS catalytic activity without increased expression of all NOS isoforms. {30:Ohsawa et al. (2004)} suggested that a moderate increase in eNOS activity associated with loss of Cav3 may result in hypertrophic cardiomyopathy. {31:Oshikawa et al. (2004)} examined the role of Cav3 in insulin signaling in a strain of Cav3 knockout mice originally developed as a model of DMD. They found Cav3 knockout led to the development of insulin resistance, as shown by decreased glucose uptake in skeletal muscles, impaired glucose tolerance, and increased serum lipids. Impairments were augmented in the presence of streptozotocin, a pancreatic beta cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of insulin receptors (INSR; {147670}) and downstream molecules, such as Irs1 ({147545}) and Akt (see AKT1; {164730}), was attenuated in the skeletal muscle of Cav3-null mice, but not in liver, without affecting Insr expression or subcellular localization. Cav3 gene transfer restored insulin signaling in skeletal muscles. {31:Oshikawa et al. (2004)} concluded that CAV3 is an enhancer of insulin signaling in skeletal muscle but it does not act as a scaffolding molecule for INSR. {28:Nixon et al. (2005)} showed that in zebrafish embryonic development Cav3 and caveolae were located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan (DAG1; {128239}) was restricted to the muscle fiber ends. Downregulation of Cav3 expression caused gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers revealed defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3 P105L ({601253.0001}), caused severe disruption of muscle differentiation. Knockdown of Cav3 resulted in a dramatic upregulation of Eng1a (see EN1; {131290}) expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. {28:Nixon et al. (2005)} concluded that Cav3 is essential to muscle development, particularly for correct intracellular organization and myoblast fusion. In COS-7 cells, {29:Ohsawa et al. (2006)} found that caveolin-3 inhibited signaling of myostatin (MSTN; {601788}), a molecule that negatively regulates skeletal muscle volume by direct interaction with and inhibition of the type I myostatin receptors ALK4 ({601300}) and ALK5 ({190181}). Doubly transgenic mice with both Cav3 deficiency and myostatin inhibition showed increased numbers and size of myofibers compared to singly Cav3-deficient mice, effectively reversing the muscle atrophy induced by Cav3 deficiency. In addition, intraperitoneal injection of a myostatin inhibitor improved functional muscle weakness in Cav3-deficient mice. {29:Ohsawa et al. (2006)} suggested that caveolin-3 normally suppresses myostatin signaling and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in this mouse model of LGMD1C. {21:Kuga et al. (2011)} found that Cav3(P104L) accumulated in the Golgi apparatus of transgenic mice and in transfected COS-7 cells. Use of wildtype and hemizygous and homozygous Cav3(P104L) mutant mice revealed a dose-dependent induction of the endoplasmic reticulum stress response by Cav3(P104L), including upregulation of the molecular chaperone Gpr78 (HSPA5; {138120}) and a mild apoptotic skeletal muscle phenotype. textSectionName animalModel geneMapExists true editHistory mgross : 04/10/2013 mgross : 4/10/2013 carol : 3/21/2013 mgross : 3/13/2013 terry : 10/4/2012 terry : 11/1/2011 carol : 11/1/2011 ckniffin : 11/1/2011 carol : 1/13/2011 alopez : 2/9/2009 wwang : 10/28/2008 carol : 7/9/2008 carol : 7/9/2008 carol : 3/10/2008 wwang : 2/26/2008 terry : 2/12/2008 wwang : 7/20/2007 wwang : 2/9/2007 ckniffin : 2/5/2007 wwang : 12/11/2006 ckniffin : 12/7/2006 wwang : 3/9/2006 terry : 2/17/2006 wwang : 2/6/2006 terry : 1/31/2006 wwang : 12/9/2005 terry : 12/7/2005 terry : 8/3/2005 wwang : 5/10/2005 ckniffin : 4/27/2005 wwang : 2/21/2005 ckniffin : 2/17/2005 ckniffin : 2/17/2005 wwang : 2/16/2005 wwang : 2/11/2005 terry : 2/4/2005 alopez : 10/7/2004 terry : 10/6/2004 carol : 9/7/2004 ckniffin : 8/30/2004 tkritzer : 2/9/2004 ckniffin : 2/3/2004 tkritzer : 1/23/2004 ckniffin : 1/20/2004 carol : 6/6/2003 ckniffin : 6/2/2003 carol : 5/22/2003 ckniffin : 5/20/2003 ckniffin : 5/20/2003 ckniffin : 5/16/2003 carol : 5/16/2003 ckniffin : 5/8/2003 cwells : 1/7/2003 ckniffin : 12/30/2002 terry : 3/28/2002 cwells : 2/13/2002 cwells : 1/23/2002 carol : 6/29/2001 carol : 6/29/2001 mgross : 6/29/2001 mgross : 6/28/2001 mgross : 6/28/2001 terry : 6/27/2001 cwells : 5/4/2001 cwells : 4/25/2001 cwells : 4/13/2001 cwells : 3/6/2001 cwells : 3/5/2001 cwells : 3/2/2001 cwells : 1/16/2001 terry : 12/14/2000 mcapotos : 10/6/2000 mcapotos : 10/3/2000 terry : 9/26/2000 terry : 2/28/2000 carol : 11/3/1999 terry : 10/26/1999 terry : 5/20/1999 carol : 3/15/1999 terry : 3/12/1999 carol : 2/10/1999 terry : 6/3/1998 terry : 5/22/1998 joanna : 5/15/1998 alopez : 4/8/1998 alopez : 4/1/1998 terry : 3/31/1998 carol : 3/21/1998 jamie : 5/29/1997 mark : 5/13/1996 mark : 5/10/1996 mark : 5/9/1996 mark : 5/9/1996 dateCreated Thu, 09 May 1996 03:00:00 EDT creationDate Mark H. Paalman : 5/9/1996 epochUpdated 1365577200 dateUpdated Wed, 10 Apr 2013 03:00:00 EDT referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12966035 publisherName HighWire Press title Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype. mimNumber 601253 referenceNumber 1 publisherAbbreviation HighWire pubmedID 12966035 source Hum. Molec. Genet. 12: 2777-2788, 2003. Note: Erratum: Hum. Molec. Genet. 13: 149 only, 2004. authors Aravamudan, B., Volonte, D., Ramani, R., Gursoy, E., Lisanti, M. P., London, B., Galbiati, F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/90050 publisherName Nature Publishing Group title Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. mimNumber 601253 referenceNumber 2 publisherAbbreviation NPG pubmedID 11431690 source Nature Genet. 28: 218-219, 2001. authors Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=14663034 publisherName HighWire Press title A CAV3 microdeletion differentially affects skeletal muscle and myocardium. mimNumber 601253 referenceNumber 3 publisherAbbreviation HighWire pubmedID 14663034 source Neurology 61: 1513-1519, 2003. authors Cagliani, R., Bresolin, N., Prelle, A., Gallanti, A., Fortunato, F., Sironi, M., Ciscato, P., Fagiolari, G., Bonato, S., Galbiati, S., Corti, S., Lamperti, C., Moggio, M., Comi, G. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10746614 publisherName HighWire Press title Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. mimNumber 601253 referenceNumber 4 publisherAbbreviation HighWire pubmedID 10746614 source Neurology 54: 1373-1376, 2000. authors Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1547-5271(06)02228-4 publisherName Elsevier Science title Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. mimNumber 601253 referenceNumber 5 publisherAbbreviation ES pubmedID 17275750 source Heart Rhythm 4: 161-166, 2007. authors Cronk, L. B., Ye, B., Kaku, T., Tester, D. J., Vatta, M., Makielski, J. C., Ackerman, M. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/1096-8628(2001)9999:9999<::AID-AJMG1168>3.0.CO;2-O publisherName John Wiley & Sons, Inc. title Mutations in the caveolin-3 gene: when are they pathogenic? mimNumber 601253 referenceNumber 6 publisherAbbreviation Wiley pubmedID 11251997 source Am. J. Med. Genet. 99: 303-307, 2001. authors de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8933338 publisherName HighWire Press title Precise localisation of 3p25 breakpoints in four patients with the 3p- syndrome. mimNumber 601253 referenceNumber 7 publisherAbbreviation HighWire pubmedID 8933338 source J. Med. Genet. 33: 842-847, 1996. authors Drumheller, T., McGillivray, B. C., Behrner, D., MacLeod, P., McFadden, D. E., Roberson, J., Venditti, C., Chorney, K., Chorney, M., Smith, D. I. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12939441 publisherName HighWire Press title Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene. mimNumber 601253 referenceNumber 8 publisherAbbreviation HighWire pubmedID 12939441 source Neurology 61: 562-564, 2003. authors Figarella-Branger, D., Pouget, J., Bernard, R., Krahn, M., Fernandez, C., Levy, N., Pellissier, J. F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.10442 publisherName John Wiley & Sons, Inc. title Consequences of a novel caveolin-3 mutation in a large German family. mimNumber 601253 referenceNumber 9 publisherAbbreviation Wiley pubmedID 12557291 source Ann. Neurol. 53: 233-241, 2003. authors Fischer, D., Schroers, A., Blumcke, I., Urbach, H., Zerres, K., Mortier, W., Vorgerd, M., Schroder, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.20119 publisherName John Wiley & Sons, Inc. title Molecular and muscle pathology in a series of caveolinopathy patients. mimNumber 601253 referenceNumber 10 publisherAbbreviation Wiley pubmedID 15580566 source Hum. Mutat. 25: 82-89, 2005. authors Fulizio, L., Nascimbeni, A. C., Fanin, M., Piluso, G., Politano, L., Nigro, V., Angelini, C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10931944 publisherName HighWire Press title Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. mimNumber 601253 referenceNumber 11 publisherAbbreviation HighWire pubmedID 10931944 source Proc. Nat. Acad. Sci. 97: 9689-9694, 2000. authors Galbiati, F., Volonte, D., Chu, J. B., Li, M., Fine, S. W., Fu, M., Bermudez, J., Pedemonte, M., Weidenheim, K. M., Pestell, R. G., Minetti, C., Lisanti, M. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10464299 publisherName HighWire Press title Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C): retention of LGMD-1C caveolin-3 mutants within the Golgi complex. mimNumber 601253 referenceNumber 12 publisherAbbreviation HighWire pubmedID 10464299 source J. Biol. Chem. 274: 25632-25641, 1999. authors Galbiati, F., Volonte, D., Minetti, C., Chu, J. B., Lisanti, M. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9325253 publisherName HighWire Press title Dissecting the interaction between nitric oxide synthase (NOS) and caveolin: functional significance of the NOS caveolin binding domain in vivo. mimNumber 601253 referenceNumber 13 publisherAbbreviation HighWire pubmedID 9325253 source J. Biol. Chem. 272: 25437-25440, 1997. authors Garcia-Cardena, G., Martasek, P., Masters, B. S. S., Skidd, P. M., Couet, J. C., Li, S., Lisanti, M. P., Sessa, W. C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ejhg.2009.103 publisherName Nature Publishing Group title Caveolinopathies: from the biology of caveolin-3 to human diseases. mimNumber 601253 referenceNumber 14 publisherAbbreviation NPG pubmedID 19584897 source Europ. J. Hum. Genet. 18: 137-145, 2010. Note: Erratum: Europ. J. Hum. Genet. 17: 1692 only, 2009. authors Gazzerro, E., Sotgia, F., Bruno, C., Lisanti, M. P., Minetti, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022-510X(08)00458-9 publisherName Elsevier Science title Phenotypic variability in a Spanish family with a caveolin-3 mutation. mimNumber 601253 referenceNumber 15 publisherAbbreviation ES pubmedID 18930476 source J. Neurol. Sci. 276: 95-98, 2009. authors Gonzalez-Perez, P., Gallano, P., Gonzalez-Quereda, L., Rivas-Infante, E., Teijeira, S., Navarro, C., Bautista-Lorite, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11115849 publisherName HighWire Press title Caveolin-3 deficiency causes muscle degeneration in mice. mimNumber 601253 referenceNumber 16 publisherAbbreviation HighWire pubmedID 11115849 source Hum. Molec. Genet. 9: 3047-3054, 2000. authors Hagiwara, Y., Sasaoka, T., Araishi, K., Imamura, M., Yorifuji, H., Nonaka, I., Ozawa, E., Kikuchi, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0006291X03024732 publisherName Elsevier Science title Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. mimNumber 601253 referenceNumber 17 publisherAbbreviation ES pubmedID 14672715 source Biochem. Biophys. Res. Commun. 313: 178-184, 2004. authors Hayashi, T., Arimura, T., Ueda, K., Shibata, H., Hohda, S., Takahashi, M., Hori, H., Koga, Y., Oka, N., Imaizumi, T., Yasunami, M., Kimura, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11001938 publisherName HighWire Press title Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. mimNumber 601253 referenceNumber 18 publisherAbbreviation HighWire pubmedID 11001938 source Hum. Molec. Genet. 9: 2335-2340, 2000. authors Herrmann, R., Straub, V., Blank, M., Kutzick, C., Franke, N., Jacob, E. N., Lenard, H.-G., Kroger, S., Voit, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.20350 publisherName John Wiley & Sons, Inc. title Autosomal recessive rippling muscle disease with homozygous CAV3 mutations. (Letter) mimNumber 601253 referenceNumber 19 publisherAbbreviation Wiley pubmedID 15668980 source Ann. Neurol. 57: 303-304, 2005. authors Kubisch, C., Ketelsen, U.-P., Goebel, I., Omran, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/ana.10501 publisherName John Wiley & Sons, Inc. title Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease. mimNumber 601253 referenceNumber 20 publisherAbbreviation Wiley pubmedID 12666119 source Ann. Neurol. 53: 512-520, 2003. authors Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=21610159 publisherName HighWire Press title Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice. mimNumber 601253 referenceNumber 21 publisherAbbreviation HighWire pubmedID 21610159 source Hum. Molec. Genet. 20: 2975-2983, 2011. authors Kuga, A., Ohsawa, Y., Okada, T., Kanda, F., Kanagawa, M., Toda, T., Sunada, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16247063 publisherName HighWire Press title Early-onset toe walking in rippling muscle disease due to a new caveolin-3 gene mutation. mimNumber 601253 referenceNumber 22 publisherAbbreviation HighWire pubmedID 16247063 source Neurology 65: 1301-1303, 2005. authors Madrid, R. E., Kubisch, C., Hays, A. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11532985 publisherName HighWire Press title The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. mimNumber 601253 referenceNumber 23 publisherAbbreviation HighWire pubmedID 11532985 source Hum. Molec. Genet. 10: 1761-1766, 2001. authors Matsuda, C., Hayashi, Y. K., Ogawa, M., Aoki, M., Murayama, K., Nishino, I., Nonaka, I., Arahata, K., Brown, R. H., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu source Chicago, Ill. 6/8/1998. mimNumber 601253 authors McNally, E. M. title Personal Communication. referenceNumber 24 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9536092 publisherName HighWire Press title Caveolin-3 in muscular dystrophy. mimNumber 601253 referenceNumber 25 publisherAbbreviation HighWire pubmedID 9536092 source Hum. Molec. Genet. 7: 871-877, 1998. authors McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=12082049 publisherName HighWire Press title Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene. mimNumber 601253 referenceNumber 26 publisherAbbreviation HighWire pubmedID 12082049 source J. Neurol. Neurosurg. Psychiat. 73: 65-67, 2002. Note: Erratum: J. Neurol. Neurosurg. Psychiat. 74: 142 only, 2003. authors Merlini, L., Carbone, I., Capanni, C., Sabatelli, P., Tortorelli, S., Sotgia, F., Lisanti, M. P., Bruno, C., Minetti, C. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0498-365 publisherName Nature Publishing Group title Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. mimNumber 601253 referenceNumber 27 publisherAbbreviation NPG pubmedID 9537420 source Nature Genet. 18: 365-368, 1998. authors Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. pubmedImages false publisherUrl http://www.nature.com articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15888488 publisherName HighWire Press title Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning. mimNumber 601253 referenceNumber 28 publisherAbbreviation HighWire pubmedID 15888488 source Hum. Molec. Genet. 14: 1727-1743, 2005. authors Nixon, S. J., Wegner, J., Ferguson, C., Mery, P.-F., Hancock, J. F., Currie, P. D., Key, B., Westerfield, M., Parton, R. G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1172/JCI28520 publisherName Journal of Clinical Investigation title Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. mimNumber 601253 referenceNumber 29 publisherAbbreviation JCI pubmedID 17039257 source J. Clin. Invest. 116: 2924-2934, 2006. authors Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. pubmedImages false publisherUrl http://www.jci.org articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14645200 publisherName HighWire Press title Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity. mimNumber 601253 referenceNumber 30 publisherAbbreviation HighWire pubmedID 14645200 source Hum. Molec. Genet. 13: 151-157, 2004. authors Ohsawa, Y., Toko, H., Katsura, M., Morimoto, K., Yamada, H., Ichikawa, Y., Murakami, T., Ohkuma, S., Komuro, I., Sunada, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15314230 publisherName HighWire Press title Insulin resistance in skeletal muscles of caveolin-3-null mice. mimNumber 601253 referenceNumber 31 publisherAbbreviation HighWire pubmedID 15314230 source Proc. Nat. Acad. Sci. 101: 12670-12675, 2004. authors Oshikawa, J., Otsu, K., Toya, Y., Tsunematsu, T., Hankins, R., Kawabe, J., Minamisawa, S., Umemura, S., Hagiwara, Y., Ishikawa, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=2705900 publisherName HighWire Press title Rippling muscle disease. mimNumber 601253 referenceNumber 32 publisherAbbreviation HighWire pubmedID 2705900 source Arch. Neurol. 46: 405-408, 1989. authors Ricker, K., Moxley, R. T., Rohkamm, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(99)00658-4 publisherName Elsevier Science title Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene: identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome. mimNumber 601253 referenceNumber 33 publisherAbbreviation ES pubmedID 10386585 source FEBS Lett. 452: 177-180, 1999. authors Sotgia, F., Minetti, C., Lisanti, M. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11159934 publisherName HighWire Press title Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity. mimNumber 601253 referenceNumber 34 publisherAbbreviation HighWire pubmedID 11159934 source Hum. Molec. Genet. 10: 173-178, 2001. authors Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8567687 publisherName HighWire Press title Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. mimNumber 601253 referenceNumber 35 publisherAbbreviation HighWire pubmedID 8567687 source J. Biol. Chem. 271: 2255-2261, 1996. authors Tang, Z., Scherer, P. E., Okamoto, T., Song, K., Chu, C., Kohtz, D. S., Nishimoto, I., Lodish, H. F., Lisanti, M. P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11805270 publisherName HighWire Press title Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy. mimNumber 601253 referenceNumber 36 publisherAbbreviation HighWire pubmedID 11805270 source Neurology 58: 323-325, 2002. Note: Erratum: Neurology 58: 839 only, 2002. authors Tateyama, M., Aoki, M., Nishino, I., Hayashi, Y. K., Sekiguchi, S., Shiga, Y., Takahashi, T., Onodera, Y., Haginoya, K., Kobayashi, K., Iinuma, K., Nonaka, I., Arahata, K., Itoyama, Y. pubmedImages false publisherUrl http://highwire.stanford.edu title A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita Thomsen. mimNumber 601253 referenceNumber 37 pubmedID 1146501 source Acta Neurol. Scand. 51: 225-232, 1975. authors Torbergsen, T. pubmedImages false articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=17060380 publisherName HighWire Press title Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. mimNumber 601253 referenceNumber 38 publisherAbbreviation HighWire pubmedID 17060380 source Circulation 114: 2104-2112, 2006. authors Vatta, M., Ackerman, M. J., Ye, B., Makielski, J. C., Ughanze, E. E., Taylor, E. W., Tester, D. J., Balijepalli, R. C., Foell, J. D., Li, Z., Kamp, T. J., Towbin, J. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10227634 publisherName HighWire Press title Phenotypic variability in rippling muscle disease. mimNumber 601253 referenceNumber 39 publisherAbbreviation HighWire pubmedID 10227634 source Neurology 52: 1453-1459, 1999. authors Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11756609 publisherName HighWire Press title A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. mimNumber 601253 referenceNumber 40 publisherAbbreviation HighWire pubmedID 11756609 source Neurology 57: 2273-2277, 2001. authors Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W. pubmedImages false publisherUrl http://highwire.stanford.edu externalLinks cmgGene false mgiHumanDisease true hprdIDs 03154 nbkIDs NBK1129;;Romano-Ward Syndrome;;;NBK1408;;Limb-Girdle Muscular Dystrophy Overview;;;NBK1385;;Caveolinopathies refSeqAccessionIDs NG_008797.2 uniGenes Hs.98303 approvedGeneSymbols CAV3 nextGxDx true locusSpecificDBs http://www.LOVD.nl/CAV3;;Limb-Girdle Muscular Dystrophy type 1C;;;http://databases.lovd.nl/genomed/home.php?select_db=CAV3;;Zhejiang University-Adinovo Center CAV3 Database dermAtlas false umlsIDs C1413146 gtr true geneIDs 859 wormbaseIDs WBGene00000301,WBGene00000302 swissProtIDs P56539 zfinIDs ZDB-GENE-050522-426 ensemblIDs ENSG00000182533,ENST00000397368 geneTests true mgiIDs MGI:107570 ncbiReferenceSequences 356582412,299115915 genbankNucleotideSequences 3179734,46854791,511857676,9930104,158257215,74354492,74353788,27879610,71518807,74354490,24270663,3089434,11258430,148171746,3059124,3150444,3150446,3150447 proteinSequences 3150449,3182930,46854792,9930105,158257216,74354493,74353789,3089435,74354491,4502589,3059125,119584349,3150445,119584350,15451860 geneticsHomeReferenceIDs gene;;CAV3;;CAV3

entryList

entry status live allelicVariantExists true epochCreated 742114800 geneMap geneSymbols FLNA, FLN1, NHBP, OPD1, OPD2, FMD, MNS, CVD1, CSBS sequenceID 15125 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked recessive phenotype Cardiac valvular dysplasia, X-linked phenotypeMimNumber 314400 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked recessive phenotype Congenital short bowel syndrome phenotypeMimNumber 300048 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance None phenotype FG syndrome 2 phenotypeMimNumber 300321 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked recessive phenotype Frontometaphyseal dysplasia phenotypeMimNumber 305620 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked dominant phenotype Heterotopia, periventricular phenotypeMimNumber 300049 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance None phenotype Heterotopia, periventricular, ED variant phenotypeMimNumber 300537 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked recessive phenotype Intestinal pseudoobstruction, neuronal phenotypeMimNumber 300048 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked dominant phenotype Melnick-Needles syndrome phenotypeMimNumber 309350 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked dominant phenotype Otopalatodigital syndrome, type I phenotypeMimNumber 311300 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance X-linked dominant phenotype Otopalatodigital syndrome, type II phenotypeMimNumber 304120 phenotypeMappingKey 3 mimNumber 300017 phenotypeInheritance None phenotype Terminal osseous dysplasia phenotypeMimNumber 300244 chromosomeLocationStart 153576899 chromosomeSort 779 chromosomeSymbol X mimNumber 300017 geneInheritance None confidence C mappingMethod REa, A, REn geneName Filamin A, alpha (actin-binding protein-280) mouseMgiID MGI:95556 mouseGeneSymbol Flna computedCytoLocation Xq28 cytoLocation Xq28 transcript uc004fkk.2 chromosomeLocationEnd 153603005 chromosome 23 contributors Patricia A. Hartz - updated : 10/15/2014 Ada Hamosh - updated : 9/2/2014 Patricia A. Hartz - updated : 7/12/2013 Ada Hamosh - updated : 5/2/2013 Ada Hamosh - updated : 11/21/2011 Cassandra L. Kniffin - updated : 1/5/2011 George E. Tiller - updated : 11/1/2010 Marla J. F. O'Neill - updated : 10/28/2010 Nara Sobreira - updated : 10/22/2010 Cassandra L. Kniffin - updated : 5/19/2009 Cassandra L. Kniffin - updated : 4/17/2009 Paul J. Converse - updated : 7/24/2008 Marla J. F. O'Neill - updated : 2/1/2008 Cassandra L. Kniffin - updated : 5/15/2007 Patricia A. Hartz - updated : 4/23/2007 Victor A. McKusick - updated : 3/27/2007 Marla J. F. O'Neill - updated : 3/15/2007 Victor A. McKusick - updated : 7/5/2006 Victor A. McKusick - updated : 6/9/2006 Cassandra L. Kniffin - updated : 6/2/2006 Marla J. F. O'Neill - updated : 5/11/2006 Paul J. Converse - updated : 4/4/2006 Marla J. F. O'Neill - updated : 12/28/2005 Victor A. McKusick - updated : 5/10/2005 Marla J. F. O'Neill - updated : 3/1/2005 Marla J. F. O'Neill - updated : 1/28/2005 Victor A. McKusick - updated : 4/8/2004 George E. Tiller - updated : 3/31/2004 Victor A. McKusick - updated : 6/5/2003 Victor A. McKusick - updated : 5/16/2003 Victor A. McKusick - updated : 3/19/2003 Cassandra L. Kniffin - updated : 11/8/2002 Patricia A. Hartz - updated : 10/28/2002 George E. Tiller - updated : 1/24/2002 Victor A. McKusick - updated : 12/18/2000 Victor A. McKusick - updated : 4/13/1999 clinicalSynopsisExists false mimNumber 300017 allelicVariantList allelicVariant status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT dbSnps rs137853310 text In the largest reported pedigree with periventricular heterotopia ({300049}) ({28:Huttenlocher et al., 1994}), {15:Fox et al. (1998)} found a C-to-T substitution in exon 3 of the FLN1 gene, which converted a CAG (gln) to a TAG (stop) codon and truncated the FLN1 protein at amino acid residue 182 of the 2,647 total amino acids in the normal protein. mutations FLNA, GLN182TER number 1 clinvarAccessions RCV000012513;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT text In affected members of a family with periventricular heterotopia ({300049}), {15:Fox et al. (1998)} found a T-to-C substitution at the second base of intron 4 in the splice donor sequence of the FLN1 gene. The mutation was predicted to cause either exon skipping or a read-through of intron 4 which would introduce a stop codon after the translation of 30 additional amino acids. The mutation was present in both a mother and daughter with periventricular heterotopia but not in the unaffected maternal grandmother. Therefore, this mutation most likely arose de novo in this pedigree in the germline of either the maternal grandmother or grandfather, both of whom were clinically unaffected. mutations FLNA, IVS4DS, T-C, +2 number 2 clinvarAccessions RCV000012514;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT text In a sporadic case of periventricular heterotopia ({300049}), {15:Fox et al. (1998)} found that the consensus splice acceptor at the end of intron 3 (3 bases from exon 4) of the FLN1 gene was mutated by a C-to-G substitution. The 'C' at position -3 is conserved among more than 70% of vertebrate splice junctions, and the 'G' at this position is seen in only 1% ({47:Shapiro and Senapathy, 1987}). The mutation appeared to have arisen de novo in the germline of the patient's mother or father. mutations FLNA, IVS3AS, C-G, -3 number 3 clinvarAccessions RCV000012515;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT text In a sporadic case of periventricular heterotopia ({300049}), {15:Fox et al. (1998)} found a G-to-A mutation at the first base of intron 2 of the FLN1 gene. The 'G' at position +1 of the intron is conserved in 100% of splice donor sequences of vertebrate genes ({47:Shapiro and Senapathy, 1987}). mutations FLNA, IVS2DS, G-A, +1 number 4 clinvarAccessions RCV000012516;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT text In a sporadic case of periventricular heterotopia ({300049}), {15:Fox et al. (1998)} found deletion of 5 bases from the coding region of exon 2 of the FLN1 gene. Bases 287-291 were removed, producing a frameshift and the introduction of a premature stop codon after the addition of 8 inappropriate amino acids. mutations FLNA, 5-BP DEL, NT287 number 5 clinvarAccessions RCV000012517;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT dbSnps rs137853311 text In a sporadic male patient with unilateral periventricular heterotopia ({300049}), epilepsy, and normal intellect, {48:Sheen et al. (2001)} found a C-to-T transition at position 1966, resulting in a leu656-to-phe (L656F) amino acid substitution in the fifth Ig-like domain of the FLN1 gene. mutations FLNA, LEU656PHE number 6 clinvarAccessions RCV000012518;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT text In a sporadic male patient with periventricular heterotopia ({300049}), epilepsy, and normal intellect, {48:Sheen et al. (2001)} found a C-to-G transversion at position 6915. This was predicted to result in termination at residue 2305 and loss of the 344 C-terminal amino acids of the FLN1 gene, which include the receptor-binding region. mutations FLNA, 5915C-G number 7 clinvarAccessions RCV000012519;;1 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT dbSnps rs28935169 text In a family with periventricular heterotopia ({300049}), {41:Moro et al. (2002)} identified a 245A-T mutation in exon 2 of the FLNA gene, leading to a glu82-to-val substitution (E82V) in the N-terminal part of the protein. The mutation likely modifies protein activity without complete loss of function. Affected females with the mutation showed a mild anatomic phenotype with few asymmetric, noncontiguous nodules on MRI, and gave birth to 5 presumably affected boys who died within a few days to several weeks or months of life. mutations FLNA, GLU82VAL number 8 clinvarAccessions RCV000012520;;1 status live name OTOPALATODIGITAL SYNDROME, TYPE I dbSnps rs28935469 text In 2 presumably unrelated families, {46:Robertson et al. (2003)} found that individuals with otopalatodigital syndrome type I (OPD1; {311300}) had a 620C-T transition in exon 3 of the FLNA gene, predicted to result in a pro207-to-leu (P207L) amino acid substitution. All affected members had bowed bones and abnormal digits as well as cleft palate. {45:Robertson et al. (2006)} identified the P207L mutation in 2 brothers with OPD1. The mutation was not identified in leukocytes of the mother, suggesting germline mosaicism. The authors emphasized the importance of the finding for genetic counseling. mutations FLNA, PRO207LEU number 9 clinvarAccessions RCV000012521;;1 status live name OTOPALATODIGITAL SYNDROME, TYPE II dbSnps rs28935470 text In 4 presumably unrelated families, each with at least 1 affected male, {46:Robertson et al. (2003)} found that individuals with otopalatodigital syndrome type II (OPD2; {304120}) had a 760G-A transition in exon 5 of the FLNA gene, predicted to cause a glu254-to-lys (E254K) amino acid substitution. All 4 patients had omphalocele, perinatal death, bowed bones, and abnormal digits; 1 also had cleft palate, and 2 had hydrocephalus. {7:Clark et al. (2009)} showed that OPD E254K fibroblast lysates had equivalent concentrations of FLNA compared with controls, and that recombinant FLNA E254K actin-binding domain (ABD) had increased in vitro F-actin binding compared with wildtype. The FLNA ABD adopts a canonical compact conformation that is not greatly disturbed by the E254K mutation either in solution or in the crystal structure. Ex vivo characterization of E254K OPD patient fibroblasts revealed that they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD affecting only specific tissues despite FLNA being widely expressed. The authors proposed a gain-of-function mechanism for the OPD disorders, which mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration. mutations FLNA, GLU254LYS number 10 clinvarAccessions RCV000079711;;1;;;RCV000012522;;1 status live name FRONTOMETAPHYSEAL DYSPLASIA dbSnps rs28935471 text In 2 affected members of a family, {46:Robertson et al. (2003)} found that frontometaphyseal dysplasia ({305620}) was related to a 3476A-C transversion in exon 22 of the FLNA gene, predicted to result in an asp1159-to-ala (D1159A) amino acid change. mutations FLNA, ASP1159ALA number 11 clinvarAccessions RCV000012523;;1 status live name MELNICK-NEEDLES SYNDROME dbSnps rs28935472 text In 5 presumably unrelated patients with Melnick-Needles syndrome ({309350}), {46:Robertson et al. (2003)} found a 3562G-A transition in exon 22 of the FLNA gene, predicted to result in an ala1188-to-thr (A1188T) amino acid change. All 5 patients had bowed bones and abnormal digits and all but one had short stature. mutations FLNA, ALA1188THR number 12 clinvarAccessions RCV000012524;;2 status live name MELNICK-NEEDLES SYNDROME dbSnps rs28935473 text In 6 presumably unrelated females with Melnick-Needles syndrome ({309350}), {46:Robertson et al. (2003)} found a 3596C-T transition in exon 22 of the FLNA gene, predicted to cause an ser1199-to-leu (S1199L) amino acid change. All 6 females were of short stature and had bowed bones and abnormal digits. {45:Robertson et al. (2006)} identified the S1199L mutation in a girl with Melnick-Needles syndrome. The girl had an unaffected twin sister who did not carry the mutation; the unaffected mother also did not carry the mutation. The twins were born with separate amniotic sacs within a single chorion, and zygosity analysis indicated a high probability that the girls were monozygotic twins. {45:Robertson et al. (2006)} concluded that the FLNA mutation occurred postzygotically in the affected twin and emphasized the importance of the finding for genetic counseling. mutations FLNA, SER1199LEU number 13 clinvarAccessions RCV000012525;;2 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED, WITH FRONTOMETAPHYSEAL DYSPLASIA text Periventricular nodular heterotopia ({300049}) and a group of skeletal dysplasias belonging to the otopalatodigital (OPD) spectrum are caused by mutation in the FLNA gene. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function in PVNH and gain of function in OPD. In a girl manifesting PVNH in combination with frontometaphyseal dysplasia ({305620}), a skeletal dysplasia of the OPD spectrum, {60:Zenker et al. (2004)} identified a de novo 7315C-A transversion in exon 45 of the FLNA gene, resulting in 2 aberrant transcripts: 1 full-length transcript with a point mutation causing a substitution of a highly conserved leu2439 residue by met (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. {60:Zenker et al. (2004)} proposed that the dual phenotype was caused by 2 functionally different, aberrant filamin A proteins and therefore represented an exceptional case of allelic gain-of-function and loss-of-function phenotypes due to a single mutation event. mutations FLNA, 7315C-A number 14 clinvarAccessions RCV000012526;;1 status live name FRONTOMETAPHYSEAL DYSPLASIA dbSnps rs137853312 text In a male patient with frontometaphyseal dysplasia ({305620}), {46:Robertson et al. (2003)} identified a 3557C-T transition in exon 22 of the FLNA gene, resulting in a ser1186-to-leu (S1186L) amino acid change. {18:Giuliano et al. (2005)} reported a 3-generation family with FMD and identified the S1186L mutation in the proband and his mother. The S1186L missense mutation in repeat 10 of the filamin A rod domain was reported in patients with frontometaphyseal dysplasia by {59:Zenker et al. (2006)}. The proposita in the family reported by {59:Zenker et al. (2006)} was a 68-year-old woman whose son had died with a diagnosis of FMD. She had had scoliosis from childhood. Prominent supraorbital ridges, hypertelorism, and a small pointed chin as well as moderate thoracolumbar scoliosis were noted. The son developed massive frontal hyperostosis from childhood leading to the diagnosis of FMD with hypertelorism, micrognathia, oligodontia, progressive sensorineural hearing loss, amblyopia, pectus excavatum, and scoliosis. During adolescence, he developed sleep apnea and had been treated with continuous positive airway pressure. {10:Ehrenstein et al. (1997)} reported the radiologic findings. The patient died unexpectedly at the age of 25 years. In contrast to most previous reports on manifesting females or carriers of the FLNA-related skeletal dysplasias, the proband showed only mild to moderate skewing of X inactivation against the mutant allele. mutations FLNA, SER1186LEU number 15 clinvarAccessions RCV000012527;;1 status live name OTOPALATODIGITAL SPECTRUM DISORDER text In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, {53:Stefanova et al. (2005)} identified heterozygosity for a 9-bp deletion from position 4904 to 4912 in exon 29 of the FLNA gene, predicting the loss of 3 amino acid residues (codons 1635-1637) in rod domain repeat 14. The mutation was not found in 2 unaffected females. The phenotype of affected females resembled frontometaphyseal dysplasia with some overlap to otopalatodigital syndrome types 1 and 2, but no signs specific for Melnick-Needles syndrome. However, males had severe extraskeletal malformations and died early, thus constituting an overlap with OPD2 and MNS. {53:Stefanova et al. (2005)} concluded that the disorder in this family is best described as an intermediate OPD spectrum phenotype that bridges the FMD and OPD2 phenotypes; see {311300}. mutations FLNA, 9-BP DEL, NT4904 number 16 clinvarAccessions RCV000012528;;1 status live name HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT text In a 13-year-old female with the Ehlers-Danlos variant of periventricular heterotopia ({300537}), {50:Sheen et al. (2005)} found a 1-bp deletion in exon 19 of the FLNA gene (2762delG). The patient showed typical features of EDS including joint hypermobility as well as myxomatous borders along the mitral and aortic valves. mutations FLNA, 1-BP DEL, 2762G number 17 clinvarAccessions RCV000012529;;1 status live name HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT text In a 16-year-old female with the Ehlers-Danlos variant of periventricular heterotopia ({300537}), {50:Sheen et al. (2005)} found a 1-bp deletion in exon 25 of the FLNA gene (4147delG). The patient had aortic aneurysm and joint hypermobility. mutations FLNA, 1-BP DEL, 4147G number 18 clinvarAccessions RCV000012530;;1 status live name HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT dbSnps rs137853313 text In a 15-year-old female with the Ehlers-Danlos variant of periventricular heterotopia ({300537}), {50:Sheen et al. (2005)} identified a 116C-G transversion in exon 2 of the FLNA gene, resulting in an ala39-to-gly (A39G) substitution. The patient had radiologic findings of periventricular heterotopia, seizures, mild cognitive delay with psychotic behavior, joint hypermobility, and aortic aneurysm. mutations FLNA, ALA39GLY number 19 clinvarAccessions RCV000012531;;1 status live name OTOPALATODIGITAL SYNDROME, TYPE I dbSnps rs137853314 text In a 26-year-old Mexican female with OPD1 ({311300}), {25:Hidalgo-Bravo et al. (2005)} identified heterozygosity for a 607G-T transversion in exon 3 of the FLNA gene, resulting in an asp203-to-tyr (D203Y) substitution in the actin binding domain. Her parents did not have the mutation. The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. mutations FLNA, ASP203TYR number 20 clinvarAccessions RCV000012532;;1 status live name HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT dbSnps rs137853315 text In 3 female patients from a 3-generation Spanish family with the Ehlers-Danlos variant of periventricular heterotopia ({300537}), {19:Gomez-Garre et al. (2006)} identified heterozygosity for a 383C-T transition in exon 3 of the FLNA gene, resulting in an ala128-to-val (A128V) substitution. The mutation was not found in unaffected family members or in 184 control chromosomes. mutations FLNA, ALA128VAL number 21 clinvarAccessions RCV000012533;;1 status live name OTOPALATODIGITAL SPECTRUM DISORDER dbSnps rs137853316 text {59:Zenker et al. (2006)} described a de novo mutation in the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome type 1 (see {311300}). The 5182G-T mutation in exon 31 was predicted to lead to the exchange of a highly conserved glycine residue at position 1728 by cysteine (G1728C) in repeat 15 of the filamin A rod domain. A short neck and deep-set ears were noted at birth. On the first day of life, presence of inspiratory stridor and episodic cyanosis led to the diagnosis of laryngomalacia and a large atrial septal defect with signs of persistent pulmonary hypertension which resolved spontaneously within 24 hours. Echocardiography showed dysplastic tricuspid valve and noncompaction of the right ventricular myocardium. The latter disappeared during infancy. The atrial septal defect was corrected at age 9 years. Conductive hearing deficit, first diagnosed in childhood, was progressive, necessitating hearing aids by the age of 12 years. At age 16 years, typical craniofacial findings of FMD were impressive supraorbital hyperostosis, hypertelorism, antimongoloid palpebral fissures, a deeply grooved philtrum, and a pointed and slightly receding chin. The terminal phalanges of thumbs and halluces were short and broad. mutations FLNA, GLY1728CYS number 22 clinvarAccessions RCV000012534;;1 status moved number 23 name MOVED TO 300017.0015 movedTo 300017.0015 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT dbSnps rs80338841 text {24:Hehr et al. (2006)} described a male patient with periventricular nodular heterotopia ({300049}) associated with a splice mutation in exon 13 of the FLNA gene (1923C-T). In addition to PVNH, the patient also presented with craniofacial features and severe constipation. {24:Hehr et al. (2006)} postulated that the predominant expression of the full-length mRNA in addition to a mutant shorter transcript lacking the 3-prime part of exon 13 had rescued a sufficient amount of FLNA protein function to result in this novel phenotype. {56:Unger et al. (2007)} suggested that the patient reported by {24:Hehr et al. (2006)} actually had FGS2 ({300321}), especially given the presence of craniofacial dysmorphic features and severe constipation. {56:Unger et al. (2007)} identified a different mutation in the FLNA gene ({300017.0028}) in a patient with FGS2. mutations FLNA, 1923C-T number 24 clinvarAccessions RCV000020423;;1;;;RCV000012536;;1 status live name INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, X-LINKED dbSnps rs80338840 text In an affected male in the Italian family of X-linked chronic idiopathic intestinal pseudoobstruction ({300048}) described originally be {2:Auricchio et al. (1996)}, {16:Gargiulo et al. (2007)} found a 2-bp deletion in exon 2 of the FLNA gene: 65-66delAC. Segregation analysis of the FLNA mutation confirmed that all obligate carriers, by pedigree or established by linkage analysis, were heterozygous for the 2-bp deletion. The mutation was absent in 164 control X chromosomes. mutations FLNA, 2-BP DEL, 65AC number 25 clinvarAccessions RCV000012537;;2 status live name OTOPALATODIGITAL SYNDROME, TYPE I dbSnps rs137853317 text In a patient with OPD type I ({311300}), {46:Robertson et al. (2003)} identified a 586C-T transition in exon 3 of the FLNA gene, resulting in an arg196-to-trp (R196W) substitution. {33:Kondoh et al. (2007)} identified the R196W mutation in a 12-year-old Japanese boy with OPD type II ({304120}). The patient had some additional unusual features, including congenital cataract, glaucoma, and congenital heart defects. {33:Kondoh et al. (2007)} noted the different phenotype caused by the same mutation and suggested that additional factors play a role in the pathogenesis of OPD spectrum disorders. mutations FLNA, ARG196TRP number 26 alternativeNames OTOPALATODIGITAL SYNDROME, TYPE II, INCLUDED clinvarAccessions RCV000012539;;1;;;RCV000012538;;1 status live name OTOPALATODIGITAL SYNDROME, TYPE II dbSnps rs137853318 text In a male fetus with otopalatodigital syndrome type II ({304120}), {40:Marino-Enriquez et al. (2007)} identified a 629G-T transversion in exon 3 of the FLNA gene, predicted to cause a cys210-to-phe (C210F) substitution within the second calponin homology domain of the actin-binding domain. Analysis of exon 3 in relatives revealed that the mutation had arisen de novo in the mother; a previous pregnancy had ended in stillbirth of a male diagnosed with OPD2. mutations FLNA, CYS210PHE number 27 clinvarAccessions RCV000012540;;1 status live name FG SYNDROME 2 dbSnps rs137853319 text In an 18-month-old boy with FG syndrome-2 (FGS2; {300321}), {56:Unger et al. (2007)} identified a hemizygous 3872C-T transition in exon 23 of the FLNA gene, resulting in a pro1291-to-leu (P1291L) substitution. His asymptomatic mother also carried the mutation, which was absent in 100 control chromosomes. The patient had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. Although the authors noted that the mutation does not affect a highly conserved residue, they referred to a patient reported by {24:Hehr et al. (2006)} with periventricular nodular heterotopia ({300049}) and a FLNA mutation ({300017.0024}), who also had craniofacial dysmorphic features and severe constipation. {56:Unger et al. (2007)} suggested that the patient reported by {24:Hehr et al. (2006)} actually had FGS2. mutations FLNA, PRO1291LEU number 28 clinvarAccessions RCV000012541;;1 status live name TERMINAL OSSEOUS DYSPLASIA dbSnps rs387907371 text In affected members of 3 families segregating terminal osseous dysplasia ({300244}), 2 of which were previously described by {5:Breuning et al. (2000)} and {3:Baroncini et al. (2007)}, and in 3 sporadic case individuals, who were previously described by {26:Horii et al. (1998)}, {9:Drut et al., (2005)}, and {5:Breuning et al. (2000)}, respectively, {54:Sun et al. (2010)} identified a causative mutation in the last nucleotide of exon 31 of the FLNA gene: a 5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (val1724_thr1739del). {54:Sun et al. (2010)} showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, {54:Sun et al. (2010)} suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. mutations FLNA, 5217G-A, 48-BP DEL number 29 clinvarAccessions RCV000012542;;2 status live name CARDIAC VALVULAR DYSPLASIA, X-LINKED dbSnps rs267606815 text In a large 5-generation Caucasian French pedigree with X-linked cardiac valvular dysplasia ({314400}), originally reported by {4:Benichou et al. (1997)} and {36:Kyndt et al. (1998)}, {35:Kyndt et al. (2007)} identified a 1910C-A transversion in exon 13 of the FLNA gene, resulting in a pro637-to-gln (P637Q) substitution at a highly conserved residue within the fourth repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. mutations FLNA, PRO637GLN number 30 clinvarAccessions RCV000012543;;1 status live name CARDIAC VALVULAR DYSPLASIA, X-LINKED dbSnps rs267606816 text In a British family with X-linked cardiac valvular dysplasia ({314400}), originally described by {42:Newbury-Ecob et al. (1993)}, {35:Kyndt et al. (2007)} identified an 862G-A transition in exon 5 of the FLNA gene, resulting in a gly288-to-arg (G288R) substitution at a highly conserved residue within the first repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. mutations FLNA, GLY288ARG number 31 clinvarAccessions RCV000012544;;1 status live name CARDIAC VALVULAR DYSPLASIA, X-LINKED dbSnps rs267606817 text In a 4-month-old boy with cardiac valvular dysplasia ({314400}), born of black African parents, {35:Kyndt et al. (2007)} identified a 2132T-A transversion in exon 14 of the FLNA gene, resulting in a val711-to-asp (V711D) substitution at a highly conserved residue in the fifth repeat consensus sequence. The patient was diagnosed prenatally with abnormally thick cardiac valves by ultrasound and fetal echocardiography; postnatal echocardiography confirmed that all valves were thickened and dystrophic, with moderate tricuspid incompetence, trivial mitral and pulmonary incompetence, and mild aortic incompetence. His carrier mother showed no evidence of cardiac involvement on clinical examination. The mutation was not found in 500 control chromosomes of white or African origin. mutations FLNA, VAL711ASP number 32 clinvarAccessions RCV000012545;;1 status live name CARDIAC VALVULAR DYSPLASIA, X-LINKED text In 2 brothers of Hong Kong Chinese origin with cardiac valvular dysplasia ({314400}), {35:Kyndt et al. (2007)} identified a 1,944-bp genomic deletion from intron 15 to intron 19 of the FLNA gene, predicting an in-frame deletion of 182 residues from val761 to gln943 that results in a truncated protein lacking repeat consensus sequences 5 to 7. The deletion was not found in 200 control chromosomes, including 100 Asian chromosomes. In the 12-year-old proband, a heart murmur was detected at 4 months of age, and echocardiography revealed myxomatous thickening of the mitral, tricuspid, and aortic valves; he had significant mitral and tricuspid regurgitation and mild aortic regurgitation. His 4-year-old brother was found to have mitral incompetence and stenosis, tricuspid regurgitation, and mild aortic regurgitation. Their 38-year-old asymptomatic carrier mother had mild aortic and pulmonary incompetence on echocardiography. mutations FLNA, 1,944-BP DEL number 33 clinvarAccessions RCV000012546;;2 status live name HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT dbSnps rs398122812 text In an 18-month-old girl with periventricular nodular heterotopia ({300049}) and seizures, {30:Jefferies et al. (2010)} identified a heterozygous 7896G-A transition in the FLNA gene, resulting in a trp2632-to-ter (W2632X) substitution. Echocardiogram showed a redundant and unobstructed pulmonary valve, a cleft in the anterior leaflet of the mitral valve with mitral regurgitation, and a patent foramen ovale with mild left-to-right shunting. There was no evidence of a persistent patent ductus arteriosus. Since there was no family history of the disorder, the mutation was assumed to have occurred de novo. {30:Jefferies et al. (2010)} noted that other cardiac defects, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva, had been reported in patients with X-linked periventricular heterotopia, and that myxomatous valvular disease (XMVD; {314400}) was also associated with FLNA mutations, but emphasized that the findings in this patient had not previously been reported. mutations FLNA, TRP2632TER number 34 clinvarAccessions RCV000022819;;1 status live name CONGENITAL SHORT BOWEL SYNDROME, X-LINKED dbSnps rs398122521 text In affected members of an Italian family segregating isolated congenital X-linked short bowel syndrome (see {300048}) and in an unrelated singleton with the disorder, {58:van der Werf et al. (2013)} identified a 2-bp deletion in exon 2 of the FLNA gene (16_17delTC). The family had been reported by {32:Kern et al. (1990)} and the single patient by {51:Siva et al. (2002)}. In the family, all obligate carriers were heterozygous for the deletion. The mother of the isolated case did not carry the deletion, indicating that it occurred as a de novo event. {58:Van der Werf et al. (2013)} stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. This mutation was absent in 92 controls and was not reported in the Exome Variant Server database. The 16_17delTC mutation is located between the first and second methionines and results in frameshift and premature termination at amino acid 103. Based on its location, {58:van der Werf et al. (2013)} predicted that the 16_17delTC mutation has a similar effect to the 65delAC mutation ({300017.0025}) reported by {2:Auricchio et al. (1996)} and {16:Gargiulo et al. (2007)}, which results in loss of only the long form of FLNA. mutations FLNA, 2-BP DEL, 16TC number 35 clinvarAccessions RCV000043474;;1 prefix * titles alternativeTitles FILAMIN, ALPHA;; FILAMIN 1; FLN1;; FLN;; ACTIN-BINDING PROTEIN 280; ABP280 preferredTitle FILAMIN A; FLNA textSectionList textSection textSectionTitle Description textSectionContent The FLNA gene encodes filamin A, a widely expressed 280-kD actin-binding protein that regulates reorganization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes, and second messengers. Filamins crosslink actin filaments into orthogonal networks in the cytoplasm and participate in the anchoring of membrane proteins to the actin cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration ({38:Maestrini et al., 1993}; {15:Fox et al., 1998}). textSectionName description textSectionTitle Cloning textSectionContent By analysis of the native ABP280 protein and cloning of the human endothelial ABP280 cDNA, {21:Gorlin et al. (1990)} demonstrated that ABP280 is a 2,647-amino acid protein with 3 functional domains: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. The N-terminal actin-binding domain of ABP280 displays strong structural and functional similarity to the N-terminal domains of dystrophin ({300377}), alpha-actinin ({102575}), and beta-spectrin ({182870}). In a search for muscle- and heart-specific isoforms that might be involved in Emery muscular dystrophy (EDMD; {310300}), {38:Maestrini et al. (1993)} identified several different ABP280 mRNAs. Two were X-linked and were produced by alternative splicing of a small exon of 24 nucleotides. Both of these were ubiquitous in distribution. At least 1 additional gene encoding an RNA more than 70% identical to ABP280 was found and was shown to map to chromosome 7 by study of human/hamster somatic cell hybrids (FLNC; {102565}). textSectionName cloning textSectionTitle Gene Function textSectionContent {57:Vadlamudi et al. (2002)} identified FLNA as a binding partner of PAK1 ({602590}) in a yeast 2-hybrid screen of a mammary gland cDNA library. By mutation analysis, they localized the PAK1-binding region in FLNA to tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1 between amino acids 52 and 132 in the conserved CDC42 ({116952})/RAC ({602048})-interacting domain. Endogenous FLNA was phosphorylated by PAK1 on ser2152 following stimulation with physiologic signaling molecules. Following stimulation, FLNA colocalized with PAK1 in membrane ruffles. The ruffle-forming activity of PAK1 was found in FLNA-expressing cells, but not in cells deficient in FLNA. Androgen receptor (AR; {313700}), a nuclear transcription factor, mediates male sexual differentiation. {37:Loy et al. (2003)} characterized a negative regulatory domain in the AR hinge region that interacts with filamin A. Filamin A interferes with AR interdomain interactions and competes with the coactivator transcriptional intermediary factor-2 (TIF2; {601993}) to downregulate AR function specifically. Although full-length filamin A is predominantly cytoplasmic, a C-terminal 100-kD fragment colocalized with AR to the nucleus. This naturally occurring filamin A fragment repressed AR transactivation and disrupted AR interdomain interactions and TIF2-activated AR function in a manner reminiscent of full-length filamin A, raising the possibility that the inhibitory effects of cytoplasmic filamin A may be transduced through this fragment, which can localize to the nucleus and form part of the preinitiation complex. This unanticipated role of filamin A added to the evidence for the involvement of cytoskeletal proteins in transcription regulation. Mutation in the X-linked FLNA gene can cause the neurologic disorder periventricular heterotopia ({300049}). Although periventricular heterotopia is characterized by a failure in neuronal migration into the cerebral cortex with consequent formation of nodules in the ventricular and subventricular zones, many neurons appear to migrate normally, even in males, suggesting compensatory mechanisms. {49:Sheen et al. (2002)} showed that, in mice, Flna mRNA was widely expressed in all brain cortical layers, whereas a homolog, Flnb ({603381}), was most highly expressed in the ventricular and subventricular zones during development. In adulthood, widespread but reduced expression of Flna and Flnb persisted throughout the cerebral cortex. Flna and Flnb proteins were highly expressed in both the leading processes and somata of migratory neurons during corticogenesis. Postnatally, Flna immunoreactivity was largely localized to the cell body, whereas Flnb was localized to the soma and neuropil during neuronal differentiation. The putative Flnb homodimerization domain strongly interacted with itself or the corresponding homologous region of Flna, as shown by yeast 2-hybrid interaction. The 2 proteins colocalized within neuronal precursors by immunocytochemistry, and the existence of Flna-Flnb heterodimers could be detected by coimmunoprecipitation. {49:Sheen et al. (2002)} suggested that FLNA and FLNB may form both homodimers and heterodimers, and that their interaction could potentially compensate for the loss of FLNA function during cortical development within patients with periventricular heterotopia. Using a yeast 2-hybrid screen, {23:Grimbert et al. (2004)} identified FLNA as a binding partner for both CMIP ({610112}) and its truncated isoform, TCMIP. Coimmunoprecipitation analysis confirmed the interactions. Immunofluorescence microscopy demonstrated homogeneous colocalization of CMIP and FLNA in the cytoplasm, but restriction of TCMIP/FLNA colocalization to points of intercellular contact. Western blot analysis showed increased FLNA expression in patients with relapse of minimal change nephrotic syndrome, a glomerular disease thought to result from abnormal T-cell activation. {23:Grimbert et al. (2004)} proposed that FLNA and CMIP/TCMIP interact in a T-cell signaling pathway. Using proteomic approaches, {55:Thelin et al. (2007)} showed that FLNA associates with the extreme CFTR ({602421}) N terminus. Cell studies revealed that filamin tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. Using yeast 2-hybrid analysis and protein pull-down assays, {31:Jimenez-Baranda et al. (2007)} showed that the human immunodeficiency virus (HIV)-1 (see {609423}) receptor CD4 ({186940}) and the HIV-1 coreceptors CCR5 ({601373}) and CXCR4 ({162643}) interacted with FLNA, which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; {601442}) phosphorylation inactivation through a RHOA ({165390})-ROCK (see {601702})-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. {31:Jimenez-Baranda et al. (2007)} concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection. {11:Ehrlicher et al. (2011)} identified the actin-binding protein filamin A (FLNA) as a central mechanotransduction element of the cytoskeleton, and reconstituted a minimal system consisting of actin filaments, FLNA, and 2 FLNA-binding partners: the cytoplasmic tail of beta-integrin ({135630}) and FilGAP ({610586}). Integrins form an essential mechanical linkage between extracellular and intracellular environments, with beta-integrin tails connecting to the actin cytoskeleton by binding directly to filamin. FilGAP is an FLNA-binding GTPase-activating protein specific for RAC, which in vivo regulates cell spreading and bleb formation. Using fluorescence loss after photoconversion, {11:Ehrlicher et al. (2011)} demonstrated that both externally imposed bulk shear and myosin-II-driven forces differentially regulate the binding of these partners to FLNA. Consistent with structural predictions, strain increases beta-integrin binding to FLNA, whereas it causes FilGAP to dissociate from FLNA, providing a direct and specific molecular basis for cellular mechanotransduction. {11:Ehrlicher et al. (2011)} concluded that their results identified a molecular mechanotransduction element within the actin cytoskeleton, revealing that mechanical strain of key proteins regulates the binding of signaling molecules. By yeast 2-hybrid and immunoprecipitation analyses, {1:Adams et al. (2012)} found that the C-terminal cytoplasmic tail of meckelin (TMEM67; {609884}) interacted with filamin A. Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA ({165390}) activity, and hyperactivation of canonical Wnt (see {606359}) signaling. {1:Adams et al. (2012)} concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling. Using yeast 2-hybrid and immunoprecipitation analyses, {27:Hu et al. (2014)} found that mouse Flna and Flnb ({603381}) interacted directly with the actin-nucleating protein Fmn1 ({136535}). The filamins and Fmn1 colocalized in cytoplasm and, to a lesser extent, nucleus, and they were coexpressed in chondrocytes. textSectionName geneFunction textSectionTitle Gene Structure textSectionContent {43:Patrosso et al. (1994)} found that the FLN1 gene is composed of 47 exons spanning approximately 26 kb. The first and part of the second exon are untranslated. The actin-binding domain at the N terminus is encoded by exons 2 to 5. The 96-amino acid repeats corresponding to the elongated backbone of the protein are encoded by the remaining 42 exons. {15:Fox et al. (1998)} stated that FLN1 consists of 48 exons covering 26 kb of genomic sequence, with a 7.9-kb open reading frame. {6:Chakarova et al. (2000)} compared the genomic structure of the filamin gene family. A previously unknown intron was found in FLNA. The comparison of FLNA with the 2 paralogs, FLNB ({603381}) and FLNC, demonstrated a highly conserved exon/intron structure with significant differences in exon 32 of all paralogs encoding the hinge I region, as well as the insertion of a novel exon 40A in FLNC only. textSectionName geneStructure textSectionTitle Mapping textSectionContent When sequences from CpG islands in the Xq28 region ({39:Maestrini et al., 1990}) were compared to sequences in databases, the gene for ABP280 was found. It is located in the distal part of Xq28, 50-60 kb downstream of the colorblindness genes. A similar localization was reported by {34:Kunst et al. (1992)}. {34:Kunst et al. (1992)} mapped the ABP280 cDNA to Xq28 by somatic hybrid cell panel analysis and fluorescence in situ hybridization (FISH). {20:Gorlin et al. (1993)} mapped the FLN gene to Xq28 by Southern blot analysis of somatic cell hybrid lines, by FISH, and by identification of portions of the FLN gene within cosmids and YACs mapped to Xq28. Specifically, the FLN gene was located within a 200-kb region between the G6PD locus at the telomeric end and the colorblindness loci and the DXS52 marker at the proximal end. Because of its similarities to dystrophin, {20:Gorlin et al. (1993)} suggested FLN as a candidate gene for 2 myopathies that map to Xq28: EDMD and Barth syndrome ({302060}). {15:Fox et al. (1998)} stated that the FLN1 gene is adjacent to the emerin gene ({300384}), which is mutant in EDMD, and the 2 genes are flanked by inverted repeats, causing the genomic segment containing these 2 genes to be present in 2 orientations in the population at large ({52:Small et al., 1997}). Notably, all large-scale rearrangements of emerin associated with EDMD failed to include FLN1, suggesting that loss of FLN1 function might be embryonically lethal. {17:Gariboldi et al. (1994)} mapped the mouse homolog to the X chromosome in a region of syntenic homology with Xq28. textSectionName mapping textSectionTitle Biochemical Features textSectionContent Crystal Structure {7:Clark et al. (2009)} determined the crystal structures of wildtype and E254K ({300017.0010})-mutant FLNA actin-binding domains (ABDs) at 2.3-angstrom resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced thermal stability for E254K. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent For a review of the disorders caused by mutations in the FLNA gene, see {44:Robertson (2005)}. X-Linked Dominant Periventricular Heterotopia X-linked dominant periventricular heterotopia ({300049}) is a disorder in which many neurons fail to migrate to the cerebral cortex and persist as nodules lining the ventricular surface. Heterozygous females with the disorder present with epilepsy and other signs, including patent ductus arteriosus (see {607411}) and coagulopathy, whereas hemizygous affected males die embryonically. {15:Fox et al. (1998)} identified the cause as mutations in the FLN1 gene ({300017.0001}-{300017.0005}), which is required for locomotion of many cell types. They demonstrated a previously unrecognized high level of expression of FLN1 in the developing cortex. Their studies demonstrated that FLN1 is required for neuronal migration to the cortex and is essential for embryogenesis. In identifying filamin-1 as the gene mutant in periventricular heterotopia, {15:Fox et al. (1998)} first narrowed the map location to an interval approximately 1 cM between marker DXS15 and the pseudoautosomal region of Xq28 by the study of additional markers. Subsequent analysis of a large duplication of Xq28 in a male patient with periventricular heterotopia ({13:Fink et al., 1997}) with a severe, albeit nonlethal, phenotype allowed the candidate interval to be refined even further. They defined the exact centromeric boundary of the duplicated segment of Xq28 as base 3377 of 3,395 bases in intron 1 of the isocitrate dehydrogenase gene (IDH3G; {300089}), approximately 600 kb distal to DXS15. However, none of the genes identified at the breakpoints or insertion site of the duplication harbored independent mutations in other patients with periventricular heterotopia. Therefore, {15:Fox et al. (1998)} concluded that the duplication of FLN1 itself was responsible for the disorder in this patient. {15:Fox et al. (1998)} studied the pattern of X inactivation in females with FLN1 mutations in nucleated peripheral blood cells. No evidence of preferential lyonization in these cells was found, suggesting that FLN1 is not required in a cell-autonomous fashion for survival of mixed peripheral white blood cells. However, an essential cell-autonomous role for FLN1 in a subset of nucleated cells or nonnucleated cells (e.g., platelets) could not be excluded. {48:Sheen et al. (2001)} performed SSCP analysis of FLN1 throughout its entire coding region in 6 periventricular heterotopia pedigrees, 31 sporadic female patients, and 24 sporadic male periventricular heterotopia patients. The authors detected FLN1 mutations in 83% of periventricular heterotopia pedigrees and 19% of sporadic females with periventricular heterotopia. Moreover, 0 of 7 females with periventricular heterotopia with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical periventricular heterotopia. Two of 24 males analyzed with periventricular heterotopia (9%) also carried FLN1 mutations. Whereas FLN1 mutations in periventricular heterotopia pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with periventricular heterotopia appear to cause either severe or partial loss of function. {50:Sheen et al. (2005)} reported 2 familial cases and 9 sporadic cases of the Ehlers-Danlos variant of periventricular heterotopia ({300537}), which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular periventricular heterotopia, indistinguishable from periventricular heterotopia due to FLNA mutations. Mutations in the FLNA gene were identified in 3 affected females ({300017.0017}-{300017.0019}); in another pedigree with no detectable exonic mutation, positive linkage to the FLNA locus on Xq28 was demonstrated, and an affected individual in this family had no detectable FLNA protein. In 3 female patients from a 3-generation Spanish family with the Ehlers-Danlos variant of periventricular heterotopia, {19:Gomez-Garre et al. (2006)} identified heterozygosity for a missense mutation in the FLNA gene ({300017.0021}). {29:Jamuar et al. (2014)} used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found that, of 8 patients carrying somatic mutations, 1 was a female patient with periventricular nodular heterotopia carrying a mutation in FLNA. Multiple Malformation Syndromes Loss-of-function mutations of FLNA are, as indicated, embryonic lethal in males but are manifest in females as a localized neuronal migration disorder, periventricular nodular heterotopia (PVNH). {46:Robertson et al. (2003)} described localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera, and urogenital tract, in 4 X-linked human disorders: otopalatodigital syndrome types I (OPD1; {311300}) and II (OPD2; {304120}), frontometaphyseal dysplasia (FMD; {305620}), and Melnick-Needles syndrome (MNS; {309350}). Several of the mutations were recurrent, and all were clustered in 4 regions of the gene: the actin-binding domain and rod domain repeats 3, 10, and 14/15. The patterns of mutation, X-chromosome inactivation, and phenotypic manifestations in this class of mutations indicated gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development. In a 26-year-old Mexican female with OPD1, {25:Hidalgo-Bravo et al. (2005)} identified a heterozygous missense mutation in the FLNA gene ({300017.0020}). The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, {53:Stefanova et al. (2005)} identified heterozygosity for a deletion in the FLNA gene ({300017.0016}). The disorder resulted in early lethality in male children in this family. The phenotype of the females was variable, rather mild, and bridged the phenotypes of various OPD spectrum disorders (see {311300}). {59:Zenker et al. (2006)} reported a gly1728-to-cys mutation ({300017.0022}) in repeat 15 of the filamin A rod domain of the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome 1. In a second family with FMD, they identified a ser1186-to-leu mutation ({300017.0015}) in a mother and her son. In contrast to most previous reports on manifesting females or carriers of FLNA-related skeletal dysplasias, the affected females in these 2 families showed only mild to moderate skewing of X-inactivation against the mutant allele. {59:Zenker et al. (2006)} suggested that the data may indicate that in females, genotype-phenotype correlation between certain FLNA mutations and OPD1 and FMD, respectively, is less strict than previously assumed. They proposed that X-inactivation is an important epigenetic modifier of the phenotype in females with the FLNA-related skeletal dysplasias. {24:Hehr et al. (2006)} described a male patient with periventricular nodular heterotopia (PVNH), craniofacial features, and severe constipation. The phenotype was associated with a splice mutation in exon 13 of the FLNA gene ({300017.0024}). {24:Hehr et al. (2006)} suggested that the patient retained enough FLNA function to avoid the usual lethality associated with loss-of-function mutations in FLNA in males. In an 18-month-old German boy with FG syndrome-2 (FGS2; {300321}), {56:Unger et al. (2007)} identified a hemizygous mutation in the FLNA gene (P1291L; {300017.0028}). He had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. The parents declined brain MRI studies. {56:Unger et al. (2007)} suggested that the patient reported by {24:Hehr et al. (2006)} actually had FGS2, due to the presence of severe constipation and dysmorphic facial features. Intestinal Pseudoobstruction/Congenital Short Bowel Syndrome In an Italian family with an X-linked recessive form of chronic idiopathic intestinal pseudoobstruction (CIIP) mapping to chromosome Xq28 (CIIPX; {300048}), {16:Gargiulo et al. (2007)} detected a 2-bp deletion in exon 2 of the FLNA gene that was present in heterozygous state in the carrier females of the family ({300017.0025}). The frameshift mutation was located between 2 close methionines at the filamin N terminus and was predicted to produce a protein truncated shortly after the first predicted methionine. Because loss-of-function FLNA mutations have been associated with X-linked dominant nodular ventricular heterotopia (PVNH; {300049}), a central nervous system migration defect that presents with seizures in females and lethality in males, it was notable that the male bearing the FLNA mutation had signs of central nervous system (CNS) involvement and possibly PVNH. To understand how the severe frameshift mutation found by {16:Gargiulo et al. (2007)} explained the CIIPX phenotype and its X-linked recessive inheritance, {16:Gargiulo et al. (2007)} transiently expressed both the wildtype and the mutant filamin in cell culture and found filamin translation to start from either of the 2 initial methionines in these conditions. Therefore, translation of a normal, shorter filamin can occur in vitro from the second methionine downstream of the 2-bp insertion. {16:Gargiulo et al. (2007)} confirmed this, demonstrating that the filamin protein was present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts. The authors concluded that the filamin N-terminal region between the initial 2 methionines is crucial for proper enteric neuron development. {8:Clayton-Smith et al. (2009)} identified a duplication of the FLNA gene in affected members of 2 families with intestinal pseudoobstruction, patent ductus arteriosus, and thrombocytopenia with giant platelets ({300048}). One of the families had been reported by {14:FitzPatrick et al. (1997)}. {58:Van der Werf et al. (2013)} reported a 2-basepair deletion in exon 2 of filamin A ({300017.0035}) in 1 family segregating X-linked congenital short bowel syndrome (see {300048}) and in an unrelated affected individual. In the family, all obligate carriers were heterozygous for the mutation; in the isolated male, the mutation had occurred as a de novo event. {58:Van der Werf et al. (2013)} stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. Terminal Osseous Dysplasia In affected members of 3 families segregating terminal osseous dysplasia ({300244}), 2 of which were previously described by {5:Breuning et al. (2000)} and {3:Baroncini et al. (2007)}, and in 3 sporadic case individuals, who were previously described by {26:Horii et al. (1998)}, {9:Drut et al., (2005)}, and {5:Breuning et al. (2000)}, respectively, {54:Sun et al. (2010)} identified a causative mutation in the FLNA gene: a 5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids ({300017.0029}). In the families, the variant segregated with the disease. {54:Sun et al. (2010)} showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, {54:Sun et al. (2010)} suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. X-Linked Cardiac Valvular Dysplasia In a large 5-generation French pedigree with X-linked cardiac valvular disease (CVD1; {314400}) mapping to Xq28, originally reported by {4:Benichou et al. (1997)} and {36:Kyndt et al. (1998)}, {35:Kyndt et al. (2007)} analyzed candidate genes and identified a missense mutation in the FLNA gene that segregated with disease (P637Q; {300017.0030}). In 3 more families with cardiac valvular disease, {35:Kyndt et al. (2007)} identified 2 different missense mutations and an in-frame deletion ({300017.0031}-{300017.0033}, respectively). No signs of periventricular heterotopia, otopalatodigital syndrome, frontometaphyseal dysplasia, or Melnick-Needles or Ehlers-Danlos syndromes were observed in these families. The missense mutations all involve highly conserved residues within the first, fourth, and fifth repeat consensus sequences of FLNA, respectively, and the deletion results in a truncated protein lacking repeats 5 through 7. textSectionName molecularGenetics textSectionTitle History textSectionContent Robert J. {22:Gorlin (2003)} was responsible for the initial description of 3 of the conditions that had been shown to be caused by mutations in the FLNA gene: OPD1, OPD2, and frontometaphyseal dysplasia. Furthermore, he correctly interpreted the genetics of Melnick-Needles syndrome as X-linked recessive rather than autosomal recessive. His son, Jed Gorlin, sequenced the FLNA gene ({21:Gorlin et al., 1990}) and mapped it to chromosome Xq28 ({20:Gorlin et al., 1993}). textSectionName history textSectionTitle Animal Model textSectionContent {12:Feng et al. (2006)} noted that hemizygous human males with FLNA mutations die prenatally or survive after birth with cardiac malformations, often dying postnatally from blood vessel rupture. They found that Flna-null mice died at midgestation with widespread hemorrhage from abnormal vessels, persistent truncus arteriosus, and incomplete cardiac septation. Conditional Flna knockout in the neural crest caused abnormalities of the cardiac outflow tract despite apparently normal migration of Flna-deficient neural crest cells. Flna-null vascular endothelial cells displayed abnormal adherens junctions and defects in cell-cell contacts. {12:Feng et al. (2006)} suggested that cell motility-independent functions of FLNA at cell-cell contacts and adherens junctions affect the development of organs. {1:Adams et al. (2012)} found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis. textSectionName animalModel geneMapExists true editHistory mgross : 10/15/2014 alopez : 9/2/2014 mgross : 7/12/2013 carol : 7/10/2013 alopez : 5/2/2013 carol : 7/17/2012 alopez : 11/28/2011 terry : 11/21/2011 wwang : 4/7/2011 carol : 1/28/2011 wwang : 1/24/2011 ckniffin : 1/5/2011 alopez : 11/5/2010 terry : 11/1/2010 terry : 11/1/2010 wwang : 10/28/2010 terry : 10/28/2010 carol : 10/27/2010 terry : 10/22/2010 terry : 10/22/2010 carol : 2/24/2010 carol : 7/28/2009 carol : 7/23/2009 wwang : 5/29/2009 ckniffin : 5/19/2009 wwang : 4/30/2009 ckniffin : 4/17/2009 carol : 1/21/2009 mgross : 8/15/2008 mgross : 8/15/2008 terry : 7/24/2008 carol : 6/10/2008 wwang : 2/7/2008 terry : 2/1/2008 terry : 9/18/2007 wwang : 5/17/2007 ckniffin : 5/15/2007 wwang : 4/23/2007 alopez : 3/28/2007 terry : 3/27/2007 wwang : 3/16/2007 terry : 3/15/2007 terry : 8/24/2006 alopez : 7/10/2006 terry : 7/5/2006 carol : 6/22/2006 alopez : 6/9/2006 wwang : 6/5/2006 ckniffin : 6/2/2006 wwang : 5/11/2006 mgross : 5/11/2006 terry : 4/4/2006 wwang : 12/29/2005 terry : 12/28/2005 wwang : 5/17/2005 wwang : 5/11/2005 terry : 5/10/2005 wwang : 3/7/2005 terry : 3/1/2005 carol : 2/3/2005 terry : 1/28/2005 ckniffin : 10/25/2004 tkritzer : 4/26/2004 tkritzer : 4/16/2004 terry : 4/8/2004 tkritzer : 3/31/2004 tkritzer : 3/31/2004 tkritzer : 6/19/2003 tkritzer : 6/13/2003 terry : 6/5/2003 tkritzer : 5/27/2003 terry : 5/16/2003 alopez : 4/2/2003 alopez : 3/21/2003 terry : 3/19/2003 mgross : 12/10/2002 carol : 11/13/2002 ckniffin : 11/8/2002 mgross : 10/28/2002 carol : 4/2/2002 cwells : 3/13/2002 cwells : 2/14/2002 cwells : 1/24/2002 mcapotos : 1/18/2001 mcapotos : 1/5/2001 terry : 12/18/2000 alopez : 9/5/2000 terry : 4/14/1999 terry : 4/13/1999 alopez : 12/4/1998 terry : 11/18/1998 dkim : 7/17/1998 mark : 4/10/1997 joanna : 1/31/1996 jason : 6/7/1994 mimadm : 2/27/1994 carol : 8/23/1993 carol : 8/16/1993 carol : 7/13/1993 carol : 7/8/1993 dateCreated Thu, 08 Jul 1993 03:00:00 EDT creationDate Victor A. McKusick : 7/8/1993 epochUpdated 1413356400 dateUpdated Wed, 15 Oct 2014 03:00:00 EDT referenceList reference articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=22121117 publisherName HighWire Press title A meckelin-filamin A interaction mediates ciliogenesis. mimNumber 300017 referenceNumber 1 publisherAbbreviation HighWire pubmedID 22121117 source Hum. Molec. Genet. 21: 1272-1286, 2012. authors Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. pubmedImages false publisherUrl http://highwire.stanford.edu title The locus for a novel syndromic form of neuronal intestinal pseudoobstruction maps to Xq28. mimNumber 300017 referenceNumber 2 pubmedID 8644737 source Am. J. Hum. Genet. 58: 743-748, 1996. authors Auricchio, A., Brancolini, V., Casari, G., Milla, P. J., Smith, V. 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J. Med. Genet. 132A: 222 only, 2005. authors Giuliano, F., Paquis-Flucklinger, V., Collignon, P., Philip, N., Bardot, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15994863 publisherName HighWire Press title Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. mimNumber 300017 referenceNumber 19 publisherAbbreviation HighWire pubmedID 15994863 source J. Med. Genet. 43: 232-237, 2006. authors Gomez-Garre, P., Seijo, M., Gutierrez-Delicado, E., Castro del Rio, M., de la Torre, C., Gomez-Abad, C., Morales-Corraliza, J., Puig, M., Serratosa, J. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71354-6 publisherName Elsevier Science title Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28. mimNumber 300017 referenceNumber 20 publisherAbbreviation ES pubmedID 8406501 source Genomics 17: 496-498, 1993. authors Gorlin, J. B., Henske, E., Warren, S. T., Kunst, C. B., D'Urso, M., Palmieri, G., Hartwig, J. H., Bruns, G., Kwiatkowski, D. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.jcb.org/cgi/pmidlookup?view=long&pmid=2391361 publisherName HighWire Press title Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring. mimNumber 300017 referenceNumber 21 publisherAbbreviation HighWire pubmedID 2391361 source J. Cell Biol. 111: 1089-1105, 1990. authors Gorlin, J. B., Yamin, R., Egan, S., Stewart, M., Stossel, T. P., Kwiatkowski, D. J., Hartwig, J. H. pubmedImages false publisherUrl http://highwire.stanford.edu source Minneapolis, Minn. 4/15/2003. mimNumber 300017 authors Gorlin, R. J. title Personal Communication. referenceNumber 22 title The filamin-A is a partner of Tc-mip, a new adapter protein involved in c-maf-dependent Th2 signaling pathway. mimNumber 300017 referenceNumber 23 pubmedID 15128042 source Molec. Immun. 40: 1257-1261, 2004. authors Grimbert, P., Valanciute, A., Audard, V., Lang, P., Guellaen, G., Sahali, D. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16299064 publisherName HighWire Press title A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter) mimNumber 300017 referenceNumber 24 publisherAbbreviation HighWire pubmedID 16299064 source J. Med. Genet. 43: 541-544, 2006. authors Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.30792 publisherName John Wiley & Sons, Inc. title A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation. mimNumber 300017 referenceNumber 25 publisherAbbreviation Wiley pubmedID 15940695 source Am. J. Med. Genet. 136A: 190-193, 2005. authors Hidalgo-Bravo, A., Pompa-Mera, E. N., Kofman-Alfaro, S., Gonzalez-Bonilla, C. R., Zenteno, J. C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19981102)80:1<1::AID-AJMG1>3.0.CO;2-8 publisherName John Wiley & Sons, Inc. title A syndrome of digital fibromas, facial pigmentary dysplasia, and metacarpal and metatarsal disorganization. mimNumber 300017 referenceNumber 26 publisherAbbreviation Wiley pubmedID 9800904 source Am. J. Med. Genet. 80: 1-5, 1998. authors Horii, E., Sugiura, Y., Nakamura, R. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=24760772 publisherName HighWire Press title Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate. mimNumber 300017 referenceNumber 27 publisherAbbreviation HighWire pubmedID 24760772 source Hum. Molec. Genet. 23: 4663-4673, 2014. authors Hu, J., Lu, J., Lian, G., Ferland, R. J., Dettenhofer, M., Sheen, V. L. pubmedImages false publisherUrl http://highwire.stanford.edu title Periventricular heterotopia and epilepsy. mimNumber 300017 referenceNumber 28 pubmedID 8290091 source Neurology 44: 51-55, 1994. authors Huttenlocher, P. R., Taravath, S., Mojtahedi, S. pubmedImages false articleUrl http://www.nejm.org/doi/abs/10.1056/NEJMoa1314432?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Somatic mutations in cerebral cortical malformations. mimNumber 300017 referenceNumber 29 publisherAbbreviation ATYPON pubmedID 25140959 source New Eng. J. Med. 371: 733-743, 2014. authors Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., {and 20 others} pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.33110 publisherName John Wiley & Sons, Inc. title Novel cardiac findings in periventricular nodular heterotopia. mimNumber 300017 referenceNumber 30 publisherAbbreviation Wiley pubmedID 20014127 source Am. J. Med. Genet. 152A: 165-168, 2010. authors Jefferies, J. L., Taylor, M. D., Rossano, J., Belmont, J. W., Craigen, W. J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ncb1610 publisherName Nature Publishing Group title Filamin-A regulates actin-dependent clustering of HIV receptors. mimNumber 300017 referenceNumber 31 publisherAbbreviation NPG pubmedID 17572668 source Nature Cell Biol. 9: 838-846, 2007. authors Jimenez-Baranda, S., Gomez-Mouton, C., Rojas, A., Martinez-Prats, L., Mira, E., Lacalle, R. A., Valencia, A., Dimitrov, D. S., Viola, A., Delgado, R., Martinez-A., C., Manes, S. pubmedImages false publisherUrl http://www.nature.com title Congenital short gut, malrotation, and dysmotility of the small bowel. mimNumber 300017 referenceNumber 32 pubmedID 2123245 source J. Pediat. Gastroent. Nutr. 11: 411-415, 1990. authors Kern, I. B., Leece, A., Bohane, T. pubmedImages false title A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype-genotype correlation. mimNumber 300017 referenceNumber 33 pubmedID 17264970 source J. Hum. Genet. 52: 370-373, 2007. authors Kondoh, T., Okamoto, N., Norimatsu, N., Uetani, M., Nishimura, G., Moriuchi, H. pubmedImages false source Am. J. Hum. Genet. 51: A21, 1992. mimNumber 300017 authors Kunst, C. B., Henske, E., Hartwig, J. H., Kwiatkowski, D. J., D'Urso, M., Bruns, G., Warren, S. T., Gorlin, J. B. title The dystrophin-like actin binding protein 280 gene maps between DXS52 and G6PD overlapping the Emery-Dreifuss muscular dystrophy locus. (Abstract) referenceNumber 34 articleUrl http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=17190868 publisherName HighWire Press title Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. mimNumber 300017 referenceNumber 35 publisherAbbreviation HighWire pubmedID 17190868 source Circulation 115: 40-49, 2007. authors Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63843-9 publisherName Elsevier Science title Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28. mimNumber 300017 referenceNumber 36 publisherAbbreviation ES pubmedID 9497244 source Am. J. Hum. Genet. 62: 627-632, 1998. authors Kyndt, F., Schott, J.-J., Trochu, J.-N., Baranger, F., Herbert, O., Scott, V., Fressinaud, E., David, A., Moisan, J.-P., Bouhour, J.-B., Le Marec, H., Benichou, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12682292 publisherName HighWire Press title Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions. mimNumber 300017 referenceNumber 37 publisherAbbreviation HighWire pubmedID 12682292 source Proc. Nat. Acad. Sci. 100: 4562-4567, 2003. authors Loy, C. J., Sim, K. S., Yong, E. L. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7689010 publisherName HighWire Press title Mapping of two genes encoding isoforms of the actin binding protein ABP-280, a dystrophin like protein, to Xq28 and to chromosome 7. mimNumber 300017 referenceNumber 38 publisherAbbreviation HighWire pubmedID 7689010 source Hum. Molec. Genet. 2: 761-766, 1993. authors Maestrini, E., Patrosso, C., Mancini, M., Rivella, S., Rocchi, M., Repetto, M., Villa, A., Frattini, A., Zoppe, M., Vezzoni, P., Toniolo, D. pubmedImages false publisherUrl http://highwire.stanford.edu title Probes for CpG islands on the distal long arm of the human X chromosome are clustered in Xq24 and Xq28. mimNumber 300017 referenceNumber 39 pubmedID 2177445 source Genomics 8: 664-670, 1990. authors Maestrini, E., Rivella, S., Tribioli, C., Purtilo, D., Rocchi, M., Archidiacono, N., Toniolo, D. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.a.31696 publisherName John Wiley & Sons, Inc. title Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G-T mutation: clinical, pathological, and molecular findings. mimNumber 300017 referenceNumber 40 publisherAbbreviation Wiley pubmedID 17431908 source Am. J. Med. Genet. 143A: 1120-1125, 2007. authors Marino-Enriquez, A., Lapunzina, P., Robertson, S. P., Rodriguez, J. I. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11914408 publisherName HighWire Press title Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene. mimNumber 300017 referenceNumber 41 publisherAbbreviation HighWire pubmedID 11914408 source Neurology 58: 916-921, 2002. authors Moro, F., Carrozzo, R., Veggiotti, P., Tortorella, G., Toniolo, D., Volzone, A., Guerrini, R. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8230166 publisherName HighWire Press title Sex linked valvular dysplasia. mimNumber 300017 referenceNumber 42 publisherAbbreviation HighWire pubmedID 8230166 source J. Med. Genet. 30: 873-874, 1993. authors Newbury-Ecob, R. A., Zuccollo, J. M., Rutter, N., Young, I. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(84)71226-2 publisherName Elsevier Science title The exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280. mimNumber 300017 referenceNumber 43 publisherAbbreviation ES pubmedID 8088819 source Genomics 21: 71-76, 1994. authors Patrosso, M. C., Repetto, M., Villa, A., Milanesi, L., Frattini, A., Faranda, S., Mancini, M., Maestrini, E., Toniolo, D., Vezzoni, P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0959-437X(05)00053-5 publisherName Elsevier Science title Filamin A: phenotypic diversity. mimNumber 300017 referenceNumber 44 publisherAbbreviation ES pubmedID 15917206 source Curr. Opin. Genet. Dev. 15: 301-307, 2005. authors Robertson, S. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201586 publisherName Nature Publishing Group title Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders. mimNumber 300017 referenceNumber 45 publisherAbbreviation NPG pubmedID 16538226 source Europ. J. Hum. Genet. 14: 549-554, 2006. authors Robertson, S. P., Thompson, S., Morgan, T., Holder-Espinasse, M., Martinot-Duquenoy, V., Wilkie, A. O. M., Manouvrier-Hanu, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng1119 publisherName Nature Publishing Group title Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. mimNumber 300017 referenceNumber 46 publisherAbbreviation NPG pubmedID 12612583 source Nature Genet. 33: 487-491, 2003. authors Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., {OPD-spectrum Disorders Clinical Collaborative Group}, Wilkie, A. O. M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3658675 publisherName HighWire Press title RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. mimNumber 300017 referenceNumber 47 publisherAbbreviation HighWire pubmedID 3658675 source Nucleic Acids Res. 15: 7155-7174, 1987. authors Shapiro, M. B., Senapathy, P. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11532987 publisherName HighWire Press title Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. mimNumber 300017 referenceNumber 48 publisherAbbreviation HighWire pubmedID 11532987 source Hum. Molec. Genet. 10: 1775-1783, 2001. authors Sheen, V. L., Dixon, P. H., Fox, J. W., Hong, S. E., Kinton, L., Sisodiya, S. M., Duncan, J. S., Dubeau, F., Scheffer, I. E., Schachter, S. C., Wilner, A., Henchy, R., {and 18 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12393796 publisherName HighWire Press title Filamin A and filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. mimNumber 300017 referenceNumber 49 publisherAbbreviation HighWire pubmedID 12393796 source Hum. Molec. Genet. 11: 2845-2854, 2002. authors Sheen, V. L., Feng, Y., Graham, D., Takafuta, T., Shapiro, S. S., Walsh, C. A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15668422 publisherName HighWire Press title Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. mimNumber 300017 referenceNumber 50 publisherAbbreviation HighWire pubmedID 15668422 source Neurology 64: 254-262, 2005. authors Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., Ganesh, V., Underwood, T., Wiley, J., Leventer, R., Vaid, R. R., Ruiz, D. E., {and 21 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jrheum.org/cgi/pmidlookup?view=long&pmid=12022328 publisherName HighWire Press title Synovial lipomatosis (lipoma arborescens) affecting multiple joints in a patient with congenital short bowel syndrome. mimNumber 300017 referenceNumber 51 publisherAbbreviation HighWire pubmedID 12022328 source J. Rheum. 29: 1088-1092, 2002. authors Siva, C., Brasington, R., Totty, W., Sotelo, A., Atkinson, J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://link.springer-ny.com/link/service/journals/00335/bibs/8n5p337.html publisherName Springer title Isolation and characterization of the complete mouse emerin gene. mimNumber 300017 referenceNumber 52 publisherAbbreviation Springer pubmedID 9107678 source Mammalian Genome 8: 337-341, 1997. authors Small, K., Wagener, M., Warren, S. T. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.30484 publisherName John Wiley & Sons, Inc. title A novel 9 bp deletion in the filamin A gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype. mimNumber 300017 referenceNumber 53 publisherAbbreviation Wiley pubmedID 15654694 source Am. J. Med. Genet. 132A: 386-390, 2005. authors Stefanova, M., Meinecke, P., Gal, A., Bolz, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(10)00311-3 publisherName Elsevier Science title Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. mimNumber 300017 referenceNumber 54 publisherAbbreviation ES pubmedID 20598277 source Am. J. Hum. Genet. 87: 146-153, 2010. authors Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI30376 publisherName Journal of Clinical Investigation title Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. mimNumber 300017 referenceNumber 55 publisherAbbreviation JCI pubmedID 17235394 source J. Clin. Invest. 117: 364-374, 2007. authors Thelin, W. R., Chen, Y., Gentzsch, M., Kreda, S. M., Sallee, J. L., Scarlett, C. O., Borchers, C. H., Jacobson, K., Stutts, M. J., Milgram, S. L. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1002/ajmg.a.31751 publisherName John Wiley & Sons, Inc. title Filamin A mutation is one cause of FG syndrome. mimNumber 300017 referenceNumber 56 publisherAbbreviation Wiley pubmedID 17632775 source Am. J. Med. Genet. 143A: 1876-1879, 2007. authors Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ncb838 publisherName Nature Publishing Group title Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. mimNumber 300017 referenceNumber 57 publisherAbbreviation NPG pubmedID 12198493 source Nature Cell Biol. 4: 681-690, 2002. authors Vadlamudi, R. K., Li, F., Adam, L., Nguyen, D., Ohta, Y., Stossel, T. P., Kumar, R. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/gim.2012.123 publisherName Nature Publishing Group title Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations. mimNumber 300017 referenceNumber 58 publisherAbbreviation NPG pubmedID 23037936 source Genet. Med. 15: 310-313, 2013. authors van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.31213 publisherName John Wiley & Sons, Inc. title Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia. mimNumber 300017 referenceNumber 59 publisherAbbreviation Wiley pubmedID 16596676 source Am. J. Med. Genet. 140A: 1069-1073, 2006. authors Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61898-9 publisherName Elsevier Science title A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. mimNumber 300017 referenceNumber 60 publisherAbbreviation ES pubmedID 14988809 source Am. J. Hum. Genet. 74: 731-737, 2004. authors Zenker, M., Rauch, A., Winterpacht, A., Tagariello, A., Kraus, C., Rupprecht, T., Sticht, H., Reis, A. pubmedImages false publisherUrl http://www.elsevier.com/ externalLinks cmgGene false mgiHumanDisease false hprdIDs 02060 nbkIDs NBK1213;;X-Linked Periventricular Heterotopia;;;NBK1393;;Otopalatodigital Spectrum Disorders refSeqAccessionIDs NG_011506.1 possumSyndromes 6428;;Periventricular nodular heterotopia, facial dysmorphism, chronic constipation uniGenes Hs.195464 approvedGeneSymbols FLNA nextGxDx true locusSpecificDBs http://www.LOVD.nl/FLNA;;Filamin A, alpha (FLNA) Mental Retardation Database flybaseIDs FBgn0014141 dermAtlas false umlsIDs C1414635 gtr true geneIDs 2316 wormbaseIDs WBGene00077342,WBGene00119391,WBGene00031907,WBGene00146262,WBGene00016006,WBGene00022048,WBGene00064604,WBGene00111046 swissProtIDs P21333 zfinIDs ZDB-GENE-030131-2145 ensemblIDs ENSG00000196924,ENST00000369850 geneTests true mgiIDs MGI:95556 ncbiReferenceSequences 160420316,160420313 genbankNucleotideSequences 53791220,45595636,194390355,53791218,18676443,34531785,37936268,312404,1203968,28242,326205157,44845049,312402,194385487,83318382,260268504,74230002,15779183,190192183,148146871,190192181,7018440,190192179,190192177,148146872,342307146,190192187,190192185,4914618,52108138,20380866,27552848,384368272,317040157,384368274 proteinSequences 18676444,15779184,53791221,194390356,45595637,194385488,53791219,1335065,160420317,1203969,28243,326205158,260268505,119593150,119593151,119593152,190192182,119593153,119593154,190192180,190192178,190192188,190192186,190192184,27552849,145207313,116241365,384368273,384368275,317040158,1657316,116063573 geneticsHomeReferenceIDs gene;;FLNA;;FLNA

entryList

entry status live allelicVariantExists true epochCreated 827395200 geneMap geneSymbols GDF5, CDMP1, SYNS2, OS5, BDA1C, SYM1B sequenceID 13632 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal recessive phenotype Acromesomelic dysplasia, Hunter-Thompson type phenotypeMimNumber 201250 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal recessive phenotype Brachydactyly, type A1, C phenotypeMimNumber 615072 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal dominant phenotype Brachydactyly, type A2 phenotypeMimNumber 112600 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal dominant phenotype Brachydactyly, type C phenotypeMimNumber 113100 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal recessive phenotype Chondrodysplasia, Grebe type phenotypeMimNumber 200700 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance Autosomal recessive phenotype Du Pan syndrome phenotypeMimNumber 228900 phenotypeMimNumber 610017 mimNumber 601146 phenotypeInheritance None phenotypicSeriesMimNumber 186500 phenotypeMappingKey 3 phenotype Multiple synostoses syndrome 2 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance None phenotype Symphalangism, proximal, 1B phenotypeMimNumber 615298 phenotypeMappingKey 3 mimNumber 601146 phenotypeInheritance None phenotype {Osteoarthritis-5} phenotypeMimNumber 612400 chromosomeLocationStart 34021148 chromosomeSort 197 chromosomeSymbol 20 mimNumber 601146 geneInheritance None confidence C mappingMethod H, Fd geneName Growth/differentiation factor-5 (cartilage-derived morphogenetic protein-1) comments form of brachydactyly type C mapping to 12q24 disproved mouseMgiID MGI:95688 mouseGeneSymbol Gdf5 computedCytoLocation 20q11.22 cytoLocation 20q11.2 transcript uc002xck.1 chromosomeLocationEnd 34026026 chromosome 20 contributors Ada Hamosh - updated : 2/12/2014 Patricia A. Hartz - updated : 12/18/2013 Marla J. F. O'Neill - updated : 3/20/2013 Marla J. F. O'Neill - updated : 2/11/2013 Marla J. F. O'Neill - updated : 12/1/2009 Cassandra L. Kniffin - updated : 10/20/2008 Ada Hamosh - updated : 7/29/2008 Marla J. F. O'Neill - updated : 7/10/2008 Patricia A. Hartz - updated : 4/30/2008 Victor A. McKusick - updated : 3/10/2008 Carol A. Bocchini - updated : 1/23/2008 Victor A. McKusick - updated : 6/8/2007 Marla J. F. O'Neill - updated : 10/18/2006 Patricia A. Hartz - updated : 8/30/2006 Marla J. F. O'Neill - updated : 4/19/2006 Victor A. McKusick - updated : 3/15/2006 Cassandra L. Kniffin - updated : 3/10/2006 Marla J. F. O'Neill - updated : 11/16/2005 Deborah L. Stone - updated : 7/23/2004 Marla J. F. O'Neill - updated : 6/8/2004 Patricia A. Hartz - updated : 3/22/2004 Victor A. McKusick -updated : 8/25/2003 Victor A. McKusick - updated : 10/16/2002 Victor A. McKusick - updated : 9/9/2002 Victor A. McKusick - updated : 8/8/2002 Paul J. Converse - updated : 6/28/2001 Victor A. McKusick - updated : 2/20/2001 Wilson H. Y. Lo - updated : 6/25/1999 Victor A. McKusick - updated : 11/13/1997 Victor A. McKusick - updated : 8/29/1997 Victor A. McKusick - updated : 8/7/1997 Alan F. Scott - updated : 9/30/1996 clinicalSynopsisExists false mimNumber 601146 allelicVariantList allelicVariant status live name ACROMESOMELIC DYSPLASIA, HUNTER-THOMPSON TYPE text In a family described by {15:Langer et al. (1989)} from the Choco District of Colombia affected with Hunter-Thompson type chondrodysplasia ({13:Hunter and Thompson, 1976}; see {201250}), {33:Thomas et al. (1996)} demonstrated that affected members were homozygous for a 22-bp tandem duplication frameshift mutation in the mature region of the CDMP1 protein. Both this form of Hunter-Thompson type chondrodysplasia and 'bp' are typified by abnormalities restricted to the limbs and the severity of the long bone shortening progresses in a proximal to distal direction. The hands and feet are most severely affected but the distal phalanges are relatively normal. mutations GDF5, 22-BP DUP number 1 clinvarAccessions RCV000008883;;1 status live name BRACHYDACTYLY, TYPE C dbSnps rs74315386 text In a family with brachydactyly type C ({113100}) previously reported by {22:Robin et al. (1997)}, {21:Polinkovsky et al. (1997)} showed that affected members were heterozygous for a C-to-T transition at nucleotide 901 of the mRNA coding sequence of the CDMP1 gene, converting the codon specifying arginine at amino acid residue 301 to a stop codon. Additional CDMP1 mutations were also found in 5 unrelated persons with presumed type C brachydactyly. The family studied by {22:Robin et al. (1997)} had 12 affected individuals across 5 generations; shortening of the second, third, and fifth middle phalanges was the principal finding. mutations GDF5, ARG301TER number 2 clinvarAccessions RCV000008884;;1 status live name CHONDRODYSPLASIA, GREBE TYPE dbSnps rs74315387 text {32:Thomas et al. (1997)} identified homozygosity for a G-to-A transition at nucleotide 1199 in the CDMP1 gene, predicted to result in a tyrosine for cysteine substitution at amino acid 400 in the mature region of CDMP-1 in a family with Grebe type chondrodysplasia ({200700}). {32:Thomas et al. (1997)} found that heterozygotes for the C400Y mutation had phenotypes resembling brachydactyly types A1 ({112500}), A4 ({112800}), or C ({113100}). mutations GDF5, CYS400TYR number 3 clinvarAccessions RCV000008885;;1 status live name CHONDRODYSPLASIA, GREBE TYPE text {9:Faiyaz-Ul-Haque et al. (2002)} described a family in which 7 males and 6 females inherited Grebe type chondrodysplasia ({200700}) in an autosomal recessive pedigree pattern. Whereas the carrier parents did not exhibit any apparent skeletal abnormalities, all affected individuals had a similar phenotype with unaffected axial and craniofacial bones. {9:Faiyaz-Ul-Haque et al. (2002)} discovered an insertion of a C at nucleotide 297 of the coding sequence in affected individuals. This insertion produced a shift in the reading frame at amino acid residue 99, causing premature termination of the polypeptide 6 amino acids downstream. mutations GDF5, 1-BP INS, 297C number 4 clinvarAccessions RCV000008886;;1 status live name FIBULAR HYPOPLASIA AND COMPLEX BRACHYDACTYLY dbSnps rs28936683 text In a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly, also known as DuPan syndrome ({228900}), {10:Faiyaz-Ul-Haque et al. (2002)} found that affected individuals were homozygous for a 1322T-C transition in the coding region of the CDMP1 gene, predicted to result in a leu441-to-pro (L441P) substitution. In a large Norwegian pedigree with brachydactyly type 2A ({112600}), {27:Seemann et al. (2005)} identified heterozygosity for the L441P mutation, which is located in the receptor interaction site. Functional studies in limb bud micromass culture and ATDC5 and C2C12 cells showed that the L441P mutant is almost inactive; biosensor interaction analysis revealed loss of binding to BMPR1A ({601229}) and BMPR1B ({603248}) ectodomains. In 22 of 37 living members of the Norwegian family of Danish descent with brachydactyly type A2 ({112600}) originally described by {19:Mohr and Wriedt (1919)}, {14:Kjaer et al. (2006)} identified heterozygosity for the L441P mutation in the GDF5 gene. Three of the mutation carriers were clinically unaffected. The mutation was also identified in a Danish individual with a similar phenotype. mutations GDF5, LEU441PRO number 5 alternativeNames BRACHYDACTYLY, TYPE A2, INCLUDED clinvarAccessions RCV000008888;;1;;;RCV000008887;;1 status live name BRACHYDACTYLY, TYPE C text {8:Everman et al. (2002)} demonstrated that the affected members of the family with brachydactyly type C ({113100}) studied by {11:Haws (1963)} had a 23-bp insertion at position 811 of the GDF5 gene as the cause of their anomaly. mutations GDF5, 23-BP INS, NT811 number 6 clinvarAccessions RCV000008889;;1 status live name CHONDRODYSPLASIA, GREBE TYPE text In 4 sibs with Grebe type acromesomelic dysplasia ({200700}) from an Omani family, {2:Al-Yahyaee et al. (2003)} identified 2 mutations in the GDF5 gene: a silent 1137A-G transition encoding lysine and a 1-bp deletion, 1144delG, predicting a frameshift resulting in loss of the biologically active C terminus of the protein. The affected sibs were homozygous for the 1144delG mutation and each parent was heterozygous. The affected sibs had normal axial skeletons, severely shortened and deformed limbs with severity increasing in a proximodistal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in 2 children, and some tarsal and metatarsal bones were absent. Only distal phalanges were present. The father and mother had short first metacarpal and middle phalanx of the fifth finger and hallux valgus, respectively. mutations GDF5, 1-BP DEL, 1144G number 7 clinvarAccessions RCV000008890;;1 status live name BRACHYDACTYLY, TYPE C dbSnps rs28936397 text In a large consanguineous Turkish kindred with brachydactyly type C ({113100}), {26:Schwabe et al. (2004)} identified a homozygous 517A-G transition in the GDF5 gene, predicting a met173-to-val substitution within a highly conserved 7-amino acid region of the CDMP1 prodomain. Homozygous offspring of consanguineous unions exhibited features of BDC consisting of brachymesophalangy and hyperphalangy of the second, third, and fifth fingers with some phenotypic variability. {26:Schwabe et al. (2004)} noted that all heterozygous mutation carriers showed mild shortening of metacarpals 4 and 5, suggesting a semidominant pattern of inheritance. mutations GDF5, MET173VAL number 8 clinvarAccessions RCV000008891;;1 status live name BRACHYDACTYLY, TYPE C text In 8 members of 3 unrelated families with type C brachydactyly ({113100}), {25:Savarirayan et al. (2003)} identified a heterozygous 1-bp insertion in the GDF5 gene, 206insG, resulting in a frameshift and premature termination 25 amino acids downstream. The change was not detected in 100 control alleles. Axial skeleton involvement was found in 4 carriers with clinical and radiographic evidence of premature vertebral endplate disease, and associated spondylolysis and spondylolisthesis were also found in 3 of these 4. Two carriers had severe bilateral vertical talus, and 1 had developmental hip dysplasia. Four members from the 3 families were also heterozygous for the 1-bp insertion, but had normal hands and feet. Two of these 4 nonpenetrant cases had what had been regarded as constitutional short stature. mutations GDF5, 1-BP INS, 206G number 9 clinvarAccessions RCV000008892;;1 status moved number 10 name MOVED TO {601446.0005} movedTo 601446.0005 status live name SYMPHALANGISM, PROXIMAL, 1B dbSnps rs74315388 text In affected members of a family with proximal symphalangism (SYM1B; {615298}), {27:Seemann et al. (2005)} identified a 1632G-T transversion in the GDF5 gene, resulting in an arg438-to-leu (R438L) substitution. Functional studies in limb bud micromass culture and ATDC5 and C2C12 cells showed increased biologic activity when compared to wildtype GDF5; biosensor interaction analysis revealed normal binding to BMPR1B ectodomain but increased binding to that of BMPR1A. In a kindred with multiple synostoses syndrome (SYNS2; {610017}) in which sequence analysis as well as linkage analysis excluded involvement of the noggin locus (NOG; {602991}), {5:Dawson et al. (2006)} found that polymorphic markers flanking the GDF5 locus cosegregated with the disease. Sequence analysis demonstrated that affected individuals in the family were heterozygous for a G-to-T transversion in the GDF5 gene that predicted an arg438-to-leu (R438L) substitution in the GDF5 protein. ({5:Dawson et al. (2006)} referred to the nucleotide substitution as 1313G-T.) Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C ({113100}), the protein encoded by the multiple synostoses syndrome allele was secreted as a mature GDF5 dimer. mutations GDF5, ARG438LEU number 11 alternativeNames MULTIPLE SYNOSTOSES SYNDROME 2, INCLUDED clinvarAccessions RCV000008893;;1;;;RCV000008894;;1 status live name FIBULAR HYPOPLASIA AND COMPLEX BRACHYDACTYLY text In a Polish mother and daughter with fibular hypoplasia and complex brachydactyly, also known as Du Pan syndrome ({228900}), {31:Szczaluba et al. (2005)} identified heterozygosity for 3 mutations on the same allele of the GDF5 gene. The mutations included a 3-bp deletion (1309delTTG), resulting in a deletion of leu437, a 1315T-A transversion, resulting in a ser439-to-thr (S439T) substitution, and a 1319A-T transversion, resulting in a his440-to-leu (H440L) substitution. All of the mutations occurred in the active domain of the protein. {31:Szczaluba et al. (2005)} postulated that the 3 mutations had a synergistic cis-acting dominant-negative effect on gene expression, resulting in autosomal dominant inheritance of the disorder in this family. mutations GDF5, 3-BP DEL, 1309TTG, SER439THR, AND HIS440LEU number 12 clinvarAccessions RCV000008895;;1 status live name MULTIPLE SYNOSTOSES SYNDROME 2 dbSnps rs121909347 text In a large Iranian family with tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism inherited in an autosomal dominant pattern (SYNS2; {610017}), {1:Akarsu et al. (1999)} found a heterozygous ser475-to-asn (S475N) mutation in GDF5 that segregated with the phenotype in 39 affected and 27 unaffected individuals. Ser475 lies in a highly conserved region of the protein. mutations GDF5, SER475ASN number 13 clinvarAccessions RCV000008896;;1 status live name SYMPHALANGISM, PROXIMAL, 1B dbSnps rs74315389 text In affected members of 2 large 5-generation Chinese families with SYM1B ({615298}), {36:Wang et al. (2006)} identified heterozygosity for a 1471G-A transition in exon 2 of the GDF5 gene, resulting in a glu491-to-lys (E491K) substitution in the TGF-beta ({190180}) domain. SSCP analysis demonstrated that the E491K mutation cosegregated with all affected individuals in both families, and the mutation was not found in 200 healthy controls. Although there was inter- and intrafamily variation of clinical features in affected individuals, penetrance was complete. mutations GDF5, GLU491LYS number 14 clinvarAccessions RCV000008897;;1 status live name OSTEOARTHRITIS SUSCEPTIBILITY 5 dbSnps rs143383 text {18:Miyamoto et al. (2007)} found significant association (p = 1.8 x 10(-13)) between a SNP in the 5-prime untranslated region (UTR) of GDF5, +104T/C ({dbSNP rs143383}), and hip osteoarthritis (OS5; {612400}) in 2 independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (p = 0.0021) and Han Chinese (p = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele (T) showing reduced activity. The findings implicated GDF5 as a susceptibility gene for osteoarthritis and suggested that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis. mutations GDF5, +104T/C ({dbSNP rs143383}) number 15 clinvarAccessions RCV000008898;;1 status live name BRACHYDACTYLY, TYPE C dbSnps rs121909348 text In affected members of a large 4-generation Han Chinese family segregating autosomal dominant brachydactyly type C (BDC; {113100}), {37:Yang et al. (2008)} identified heterozygosity for a 1461T-G transversion in the GDF5 gene, resulting in a tyr487-to-ter (Y487X) substitution predicted to truncate the GDF5 precursor polypeptide by 15 amino acids, deleting 2 of 7 C-terminal cysteine residues. The mutation was not detected in an unaffected family member or in 50 controls. mutations GDF5, TYR487TER number 16 clinvarAccessions RCV000008899;;1 status live name SYMPHALANGISM, PROXIMAL, 1B dbSnps rs121909349 text In the proband of a 4-generation Han Chinese family with autosomal dominant proximal symphalangism (SYM1B; {615298}), who was negative for mutation in the NOG gene ({602991}), {37:Yang et al. (2008)} identified heterozygosity for a 1118T-G transversion in the GDF5 gene, resulting in a leu373-to-arg (L373R) substitution at a highly conserved residue in the GDF5 prodomain. The mutation was not detected in 3 unaffected family members or in 50 controls. mutations GDF5, LEU373ARG number 17 clinvarAccessions RCV000008900;;1 status live name FIBULAR HYPOPLASIA AND COMPLEX BRACHYDACTYLY dbSnps rs121909350 text In a 20-month-old boy with mild fibular hypoplasia and complex brachydactyly ({228900}), {7:Douzgou et al. (2008)} identified compound heterozygosity for 2 mutations in the GDF5 gene: a 1133G-A transition resulting in an arg378-to-gln (R378Q) substitution inherited from the father, and a 1306C-A transversion resulting in a pro436-to-thr (P436T; {601146.0019}) substitution inherited from the mother. The R378Q substitution is located at the end of the prodomain within the recognition motif at the processing site of GDF5 where the precursor protein is cleaved and was predicted to result in at least partial loss of function. The P436T substitution is located within the mature domain of GDF5 and was predicted to interfere with binding to BMPR1B ({603248}). The patient's mother was unaffected, whereas the father had very mild radiographic features of brachymesophalangy of the hand digits. mutations GDF5, ARG378GLN number 18 clinvarAccessions RCV000008901;;1 status live name FIBULAR HYPOPLASIA AND COMPLEX BRACHYDACTYLY dbSnps rs121909351 text See {7:Douzgou et al. (2008)} and {601146.0018}. mutations GDF5, PRO436THR number 19 clinvarAccessions RCV000008902;;1 status live name BRACHYDACTYLY, TYPE A1, C dbSnps rs397514519 text In 3 affected sibs from a consanguineous French Canadian family with type A1 brachydactyly (BDA1C; {615072}), {3:Byrnes et al. (2010)} identified homozygosity for a 1195C-T transition in the GDF5 gene, resulting in an arg399-to-cys (R399C) substitution at a highly conserved residue in the mature active region. The mutation was not found in 2 unaffected sisters or in 400 control chromosomes; the proband's son, who was mildly affected, carried the R399C mutation in heterozygosity, consistent with a semidominant pattern of inheritance. mutations GDF5, ARG399CYS number 20 clinvarAccessions RCV000032711;;1 status live name BRACHYDACTYLY, TYPE A2 dbSnps rs397514668 text In 14 affected individuals from a 6-generation family with type A2 brachydactyly (BDA2; {112600}), {20:Ploger et al. (2008)} identified heterozygosity for a 1139G-A transition in the GDF5 gene, resulting in an arg380-to-gln (R380Q) substitution at the P2 position of the subtilisin-like proprotein convertase processing site. The mutation was not found in unaffected family members. Analysis of the R380Q mutant in chicken micromass cultures demonstrated secretion of the mutant but showed a severe reduction in biologic activity. Western blot analyses showed that the mutation interferes with GDF5 processing, and studies in E. coli confirmed that unprocessed proGDF5 is virtually inactive. mutations GDF5, ARG380GLN number 21 clinvarAccessions RCV000033861;;1 prefix * titles alternativeTitles CARTILAGE-DERIVED MORPHOGENETIC PROTEIN 1; CDMP1;; LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 4; LAP4;; LPS-ASSOCIATED PROTEIN 4;; BONE MORPHOGENETIC PROTEIN 14; BMP14 preferredTitle GROWTH/DIFFERENTIATION FACTOR 5; GDF5 textSectionList textSection textSectionTitle Cloning textSectionContent The TGF-beta (TGFB; {191080}) superfamily comprises a number of functionally diverse growth factors/signaling molecules that elicit their response upon binding to serine-threonine kinase receptors. {29:Storm et al. (1994)} identified 3 novel members of the TGFB superfamily in mice, designated Gdf5, Gdf6 ({601147}), and Gdf7 ({604651}), which are closely related to the bone morphogenetic proteins (see BMP9, {605120}). Each of the deduced proteins contains a putative polybasic proteolytic processing site followed by a C-terminal region containing 7 conserved cysteine residues. High sequence identity among the Gdf proteins suggested that they comprise a novel TGFB subfamily. By degenerate PCR and 3-prime RACE of a human embryo cDNA library, followed by screening a fibroblast cDNA library, {12:Hotten et al. (1994)} cloned GDF5. The deduced 501-amino acid protein contains a potential N-glycosylation site in the N-terminal propeptide region and a putative polybasic processing site (RRKKRR) in the C terminus. Upon processing, the mature GDF5 protein contains 120 amino acids and has a calculated molecular mass of 13.6 kD. The mouse and human GDF5 precursor proteins share 91% identity, and the mature proteins differ in only 1 amino acid. The putative N-glycosylation site in the propeptide and all 10 cysteines are conserved. Following infection with recombinant vaccinia virus carrying GDF5 cDNA, osteosarcoma cells expressed GDF5 at an apparent molecular mass of about 15 kD under reducing conditions. GDF5 showed an apparent molecular mass of about 25 kD under nonreducing conditions, indicating that GDF5 is expressed as a dimer. An apparent 70-kD protein, likely the uncleaved precursor protein, was also found under reducing conditions. {4:Chang et al. (1994)} also isolated and characterized human GDF5, which they designated CDMP1, as well as human GDF6 (CDMP2). GDF6 is predominantly expressed at sites of skeletal morphogenesis. Expression is normally restricted to the primordial cartilage of appendicular skeleton, with little expression in the axial skeleton such as vertebrae and ribs. {30:Storm and Kingsley (1996)} found that Gdf5 was expressed in a pattern of transverse stripes within many skeletal precursors in developing mouse limb. The number, location, and time of appearance of these stripes corresponded to sites where joints would later form between skeletal elements. textSectionName cloning textSectionTitle Gene Structure textSectionContent {12:Hotten et al. (1994)} determined that the GDF5 gene contains 2 exons. textSectionName geneStructure textSectionTitle Mapping textSectionContent In the mouse, the brachypodism (bp) mutant was mapped to linkage group V ({23:Runner, 1959}), which is known to be located on the distal region of mouse chromosome 2. {29:Storm et al. (1994)} mapped the mouse Gdf5 gene to the same region of chromosome 2, between the agouti and Src loci. This region shares syntenic homology with human chromosome 20q11.2. {16:Lin et al. (1996)} mapped the GDF5 gene to 20q11.2, where it is tightly linked to D20S191 and D20S195. textSectionName mapping textSectionTitle Gene Function textSectionContent CD14 ({158120}) and lipopolysaccharide (LPS)-binding protein (LBP; {151990}) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; {603030}). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, {34:Triantafilou et al. (2001)} identified 4 diverse proteins, heat shock cognate protein (HSPA8; {600816}), HSP90A (HSPCA; {140571}), chemokine receptor CXCR4 ({162643}), and GDF5, on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. {34:Triantafilou et al. (2001)} proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens. {28:Settle et al. (2003)} found that mouse Gdf5, Gdf6, and Gdf7 ({604651}) are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. All were expressed in stripes across developing skeletal condensations before the precursors had separated into obviously distinct cartilage elements and joints. The expression of Gdf5 and Gdf6 was much more restricted than that of Gdf7. textSectionName geneFunction textSectionTitle Biochemical Features textSectionContent {33:Thomas et al. (1996)} stated that CDMP1 is synthesized in a 'pro' form that subsequently dimerizes by a single interchain disulfide bond. A mature biologically active region is formed following cleavage at a characteristic arg-X-X-arg site. The overall structure of the mature protein is determined by the invariable spacing of 7 cysteine residues, 1 of which is involved in the formation of the interchain disulfide bond. The importance of the cysteine residues in determining the structure and ultimate function of TGF-beta superfamily members has been inferred from x-ray and NMR studies and demonstrated by site-directed mutagenesis. Replacement of any 1 of the 7 conserved cysteine residues of TGF-beta-1 by a serine produces a dramatic reduction of activity. The mutation in Hunter-Thompson type chondrodysplasia occurs in the mature region at position 1475, 11 amino acids after the third cysteine, disrupting the highly conserved 7 cysteine pattern, and results in a mature protein where only the first 62 out of 120 amino acids are in-frame. The 43 out-of-frame amino acids share no identity to the normal protein. The authors speculated that differences observed between Hunter-Thompson type chondrodysplasia and the brachypodism (bp) mouse phenotype (caused by mutation in the Gdf5 gene) may be due to genetic background, differences between human and mouse skeletal development, or interspecies variation in expression patterns of other compensatory gene products. textSectionName biochemicalFeatures textSectionTitle Molecular Genetics textSectionContent Acromesomelic Dysplasia, Hunter-Thompson Type {33:Thomas et al. (1996)} demonstrated a mutation in the CDMP1 gene in acromesomelic chondrodysplasia of the Hunter-Thompson type ({201250}). This disorder is phenotypically similar to murine brachypodism (bp), a recessive trait due to mutations in Gdf5 ({29:Storm et al., 1994}). Chondrodysplasia, Grebe Type {32:Thomas et al. (1997)} showed that a cys400-to-tyr mutation (C400Y; {601146.0003}) in the CDMP1 gene resulted in Grebe type chondrodysplasia ({200700}). They found that the mutant protein is not secreted and is inactive in vitro. It produced a dominant-negative effect by preventing the secretion of other, related bone morphogenetic proteins (BMPs). This appeared to occur through the formation of heterodimers. The mutation and its proposed mechanism of action provided the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis. The role of a dominant-negative mutation in a recessive disorder was illustrated. Brachydactyly Type C {21:Polinkovsky et al. (1997)} identified heterozygosity for an arg301-to-ter (R301X; {601146.0002}) mutation in the CDMP1 in autosomal dominant brachydactyly type C ({113100}). {8:Everman et al. (2002)} showed that a family whose type C brachydactyly was initially thought to map to chromosome 12 actually had a 23-bp insertion mutation in the CDMP1 gene ({601146.0006}). They reported heterozygous CDMP1 mutations in 9 additional probands/families with brachydactyly type C and presented in vitro expression data suggesting functional haploinsufficiency as the mechanism of mutational effect that caused brachydactyly type C. {26:Schwabe et al. (2004)} described a large consanguineous Turkish kindred with a semidominant form of brachydactyly type C in which affected members were homozygous for a missense mutation ({601146.0008}) and heterozygous carriers of the mutation had mild shortening of metacarpals 4 and 5. {37:Yang et al. (2008)} analyzed the GDF5 gene in 2 Han Chinese families, 1 with brachydactyly type C and 1 with proximal symphalangism, and identified heterozygosity for a Y487X mutation ({601146.0016}) and an L373R mutation ({601146.0017}), respectively. Mature GDF5 protein was detected in supernatant derived from L373R-transfected cells, but not in supernatant from Y487X-transfected cells, indicating that the 2 mutations led to different fates of the mutant GDF5 proteins, thereby producing distinct limb phenotypes. Fibular Hypoplasia and Complex Brachydactyly Fibular hypoplasia and complex brachydactyly ({228900}), otherwise known as Du Pan syndrome, is an autosomal recessive trait characterized by either reductions or absence of bones in the limbs and appendicular bone dysmorphogenesis with unaffected axial bones. Because of similarities to the Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia, {10:Faiyaz-Ul-Haque et al. (2002)} examined genomic DNA from a Pakistani family with DuPan syndrome for mutations in the CDMP1 gene and identified homozygosity for an L441P mutation ({601146.0005}). Brachydactyly Type A2 In a family with type A2 brachydactyly (BDA2; {112600}) and another with proximal symphalangism (SYM1B; {615298}), {27:Seemann et al. (2005)} identified missense mutations in the GDF5 gene (L441P and R438L, {601146.0011}, respectively). Functional studies revealed loss of binding to the BMPR1A ({601299}) and BMPR1B ({603248}) ectodomains for the L441P mutant, whereas the R438L mutant had normal binding to BMPR1B and increased binding to BMPR1A; binding to NOG ({602991}) was normal for both. {27:Seemann et al. (2005)} concluded that the brachydactyly A2 phenotype is caused by inhibition of ligand-receptor interaction, whereas the symphalangism phenotype is caused by a loss of receptor-binding specificity, resulting in a gain of function due to the acquisition of BMP2-like properties. In the original BDA2 family reported by {19:Mohr and Wriedt (1919)}, {14:Kjaer et al. (2006)} identified heterozygosity for the L441P mutation in the GDF5 gene. In 14 affected individuals from a 6-generation family with BDA2 in whom no mutations in the BMPR1B gene were identified, {20:Ploger et al. (2008)} identified heterozygosity for a missense mutation in the GDF5 gene (R380Q; {601164.0021}). Functional analysis demonstrated that the R380Q mutation results in reduced GDF5 function caused by diminished proteolytic cleavage, which is a precondition to generate biologically active GDF5. Multiple Synostoses Syndrome 2 Multiple synostoses syndrome (SYNS1; {186500}) is characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the noggin gene (NOG; {602991}) can be responsible for the disorder. {1:Akarsu et al. (1999)} described a large Iranian family with a multiple synostosis syndrome, which they designated SYNS2 ({610017}), mapping to chromosome 20q11.2. They found a heterozygous missense mutation in the GDF5 gene ({601146.0014}) as the cause of the disorder. In a family with multiple synostoses syndrome in which linkage to the noggin locus had been excluded, {5:Dawson et al. (2006)} found that polymorphic markers flanking the GDF5 locus segregated with the disorder. Sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicted an R438L substitution in the GDF5 protein ({601146.0011}). Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple synostoses syndrome allele was secreted as a mature GDF5 dimer. Proximal Symphalangism In affected members of 2 large 5-generation Chinese families with SYM1B ({615298}), {36:Wang et al. (2006)} identified heterozygosity for a missense mutation in the GDF5 gene (E491K; {601146.0014}). In a Han Chinese family with proximal symphalangism, {37:Yang et al. (2008)} found a L373R mutation in the GDF5 gene ({601146.0017}). Mature GDF5 protein was detected in supernatant derived from L373R-transfected cells. In a family with proximal symphalangism, {27:Seemann et al. (2005)} identified a R438L mutation in the GDF5 gene ({601146.0011}). Functional studies revealed that the R438L mutant had normal binding to BMPR1B ({603248}) and increased binding to BMPR1A ({601229}), with normal binding to NOG ({602991}). {27:Seemann et al. (2005)} concluded that the symphalangism phenotype is caused by a loss of receptor-binding specificity, resulting in a gain of function due to the acquisition of BMP2-like properties. These authors also detected and functionally characterized a missense mutation in a family with type A2 brachydactyly (see {601146.0005}). Osteoarthritis Susceptibility 5 Osteoarthritis (see {165720}), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. {18:Miyamoto et al. (2007)} found that a SNP in the 5-prime untranslated region (UTR) of the GDF5 gene ({601146.0015}) is associated with osteoarthritis in Asian populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. The findings implicated GDF5 as a susceptibility gene for osteoarthritis and suggested that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis. {18:Miyamoto et al. (2007)} cited preliminary evidence that mice carrying a dominant/negative mutation in Gdf5 show osteoarthritic phenotypes. The authors concluded that their findings pointed to an important role for GDF5 in articular cartilage homeostasis and indicated that decreased GDF5 expression may lead to susceptibility to osteoarthritis. Therefore, increased GDF5 expression or enhancement of its downstream signal could help to prevent osteoarthritis. To identify rare variants in GDF5 that could influence OA susceptibility either by acting as independent risk factors or by modulating the influence of {dbSNP rs143383} ({601146.0015}), {6:Dodd et al. (2013)} performed deep sequencing of GDF5 and identified a C-to-A transversion in the proximal promoter, 41 basepairs upstream of the transcription start site. This promoter variant was predicted to affect transcription factor binding and may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T allele of {dbSNP rs143383}. Using reporter constructs, {6:Dodd et al. (2013)} demonstrated that the transversion leads to increased gene expression to such a degree that the A allele is able to compensate for the reduced expression mediated by the T allele of {dbSNP rs143383}. {6:Dodd et al. (2013)} then used electrophoretic mobility shift assays to identify YY1 ({600013}) as a trans-acting factor that differentially binds to the alleles of the -41-bp variant, with more avid binding to the A allele. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. Brachydactyly, Type A1, C In 3 affected sibs from a consanguineous French Canadian family with type A1 brachydactyly mapping to chromosome 20q11 (BDA1C; {615072}), {3:Byrnes et al. (2010)} identified homozygosity for a missense mutation in the candidate gene GDF5 (R399C; {601146.0020}). The proband's son, who had a milder phenotype, was heterozygous for the R399C mutation, consistent with a semidominant pattern of inheritance. Stature as a Quantitative Trait See STQTL14 ({612228}) for a discussion of genetic variation influencing height associated with the GDF5-UQCC ({611797}) locus. textSectionName molecularGenetics textSectionTitle Animal Model textSectionContent {29:Storm et al. (1994)} identified mutations in the Gdf5 gene as the cause of the mouse brachypodism (bp) phenotype; bp null mutations alter bone lengths and the number of segments in the digits of all 4 limbs, but do not affect ear, sternum, rib, or vertebral morphology. {30:Storm and Kingsley (1996)} found that null mutations in Gdf5 disrupted formation of more than 30% of synovial joints in mouse limb, leading to complete or partial fusions between skeletal elements and changes in the pattern of repeating structures in the digits, wrists, and ankles. Mice carrying a null mutation in both Gdf5 and Bmp5 ({112265}) showed additional abnormalities not observed in either of the single mutants, including disruption of sternebrae within the sternum and abnormal formation of fibrocartilaginous joints between sternebrae and ribs. {35:Tsumaki et al. (1999)} generated transgenic mice expressing recombinant CDMP1. These mice died before or just after birth and exhibited chondrodysplasia with expanded primordial cartilage, which consisted of an enlarged hypertrophic zone and a reduced proliferating chondrocyte zone, not only in the limbs but also in the axial skeleton. Histologically, CDMP1 increased the number of chondroprogenitor cells and accelerated chondrocyte differentiation to hypertrophy. Moreover, ectopic expression of CDMP1 in the notochord before onset of chondrogenesis inhibited mesenchymal cell condensation around the notochord, which led to failure of vertebral body formation. {28:Settle et al. (2003)} found that Gdf5/Gdf6 double-mutant mice survived to birth in normal mendelian ratios, but only a small percentage survived to adulthood. The double-mutant mice had skeletal defects not seen in either Gdf5 or Gdf6 single mutants. Many limb bones were severely reduced or absent, several limb joints failed to form, and the vertebral column of 2 of 7 mice showed severe scoliosis. In a mutant line of mice (M100451) exhibiting a brachypodism phenotype, {17:Masuya et al. (2007)} identified a W408R substitution in a highly conserved region of the active signaling domain of the Gdf5 protein. The mutation was semidominant, with heterozygotes showing brachypodism and ankylosis, whereas homozygotes showed much more severe brachypodism, ankylosis of the knee joint, and malformation of the elbow joint with early-onset osteoarthritis. Functional studies revealed that W408R Gdf5 protein is secreted and dimerizes normally, but inhibits the function of wildtype Gdf5 protein in a dominant-negative fashion. {17:Masuya et al. (2007)} concluded that Gdf5 plays a critical role in joint formation and development of osteoarthritis, and that M100451 mouse should serve as a good model for osteoarthritis. Using mice with skeletal muscle-specific knockout or knockdown of BMP signaling molecules, {24:Sartori et al. (2013)} found that BMP signaling, acting via Smad1 ({601595}), Smad5 ({603110}), and Smad8 (SMAD9; {603295}) (Smad1/5/8) and Smad4 ({600993}), regulated muscle mass. Inhibition of BMP signaling caused muscle atrophy, abolished the hypertrophic phenotype of myostatin (MSTN; {601788})-deficient mice, and exacerbated the muscle-wasting effects of denervation and fasting. Bmp14 was required to prevent excessive muscle loss following denervation. The BMP-Smad1/5/8-Smad4 pathway negatively regulated Fbxo30 ({609101}), a ubiquitin ligase required for muscle loss. Inhibition of Fbxo30 protected denervated muscle from atrophy and blunted atrophy in Smad4-deficient muscle. {24:Sartori et al. (2013)} concluded that BMP signaling is the dominant pathway controlling muscle mass and that the hypertrophic phenotype caused by myostatin inhibition results from unrestrained BMP signaling. textSectionName animalModel geneMapExists true editHistory carol : 11/20/2014 alopez : 2/12/2014 alopez : 2/12/2014 mgross : 12/18/2013 mcolton : 12/13/2013 alopez : 7/8/2013 carol : 3/20/2013 carol : 2/11/2013 terry : 8/6/2012 terry : 5/27/2010 wwang : 12/14/2009 terry : 12/1/2009 carol : 10/28/2009 carol : 12/4/2008 alopez : 11/14/2008 alopez : 11/13/2008 wwang : 10/22/2008 ckniffin : 10/20/2008 alopez : 8/7/2008 terry : 7/29/2008 wwang : 7/14/2008 terry : 7/10/2008 wwang : 4/30/2008 mgross : 4/30/2008 terry : 4/30/2008 alopez : 3/13/2008 alopez : 3/13/2008 terry : 3/10/2008 carol : 1/23/2008 alopez : 6/28/2007 terry : 6/8/2007 wwang : 10/19/2006 terry : 10/18/2006 carol : 8/30/2006 terry : 8/30/2006 carol : 6/9/2006 carol : 4/24/2006 wwang : 4/20/2006 terry : 4/19/2006 alopez : 3/29/2006 alopez : 3/17/2006 terry : 3/15/2006 carol : 3/13/2006 ckniffin : 3/10/2006 wwang : 11/18/2005 terry : 11/16/2005 tkritzer : 7/29/2004 terry : 7/23/2004 carol : 6/9/2004 terry : 6/8/2004 mgross : 3/31/2004 terry : 3/22/2004 carol : 9/17/2003 tkritzer : 8/27/2003 tkritzer : 8/26/2003 terry : 8/25/2003 tkritzer : 10/28/2002 carol : 10/25/2002 tkritzer : 10/23/2002 terry : 10/16/2002 alopez : 9/9/2002 alopez : 9/9/2002 tkritzer : 8/13/2002 tkritzer : 8/9/2002 terry : 8/8/2002 mgross : 6/28/2001 mcapotos : 2/27/2001 mcapotos : 2/21/2001 mcapotos : 2/20/2001 mcapotos : 2/20/2001 carol : 6/25/1999 dkim : 9/11/1998 alopez : 7/27/1998 alopez : 7/23/1998 terry : 6/4/1998 terry : 11/14/1997 terry : 11/13/1997 terry : 11/13/1997 dholmes : 9/30/1997 jenny : 9/3/1997 terry : 8/29/1997 terry : 8/29/1997 dholmes : 8/14/1997 terry : 8/11/1997 terry : 8/7/1997 terry : 8/7/1997 mark : 7/8/1997 alopez : 7/3/1997 mark : 9/30/1996 terry : 5/24/1996 terry : 3/29/1996 mark : 3/25/1996 dateCreated Thu, 21 Mar 1996 03:00:00 EST creationDate Victor A. McKusick : 3/21/1996 epochUpdated 1416470400 dateUpdated Thu, 20 Nov 2014 03:00:00 EST referenceList reference source Am. J. Hum. Genet. 65 (suppl.): A281 only, 1999. mimNumber 601146 authors Akarsu, A. N., Rezaie, T., Demirtas, M., Farhud, D. D., Sarfarazi, M. title Multiple synostosis type 2 (SYNS2) maps to 20q11.2 and caused by a missense mutation in the growth/differentiation factor 5 (GDF5). (Abstract) referenceNumber 1 articleUrl http://dx.doi.org/10.1002/ajmg.a.20256 publisherName John Wiley & Sons, Inc. title Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family. mimNumber 601146 referenceNumber 2 publisherAbbreviation Wiley pubmedID 12900894 source Am. J. Med. Genet. 121A: 9-14, 2003. authors Al-Yahyaee, S. A. S., Al-Kindi, M. N., Habbal, O., Kumar, D. S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/humu.21338 publisherName John Wiley & Sons, Inc. title Mutations in GDF5 presenting as semidominant brachydactyly A1. mimNumber 601146 referenceNumber 3 publisherAbbreviation Wiley pubmedID 20683927 source Hum. Mutat. 31: 1155-1162, 2010. authors Byrnes, A. M., Racacho, L., Nikkel, S. M., Xiao, F., MacDonald, H., Underhill, T. M., Bulman, D. E. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7961761 publisherName HighWire Press title Cartilage-derived morphogenetic proteins: new members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. mimNumber 601146 referenceNumber 4 publisherAbbreviation HighWire pubmedID 7961761 source J. Biol. Chem. 269: 28227-28234, 1994. authors Chang, S. C., Hoang, B., Thomas, J. T., Vukicevic, S., Luyten, F. P., Ryba, N. J. P., Kozak, C. A., Reddi, A. H., Moos, M., Jr. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63708-2 publisherName Elsevier Science title GDF5 is a second locus for multiple-synostosis syndrome. mimNumber 601146 referenceNumber 5 publisherAbbreviation ES pubmedID 16532400 source Am. J. Hum. Genet. 78: 708-712, 2006. authors Dawson, K., Seeman, P., Sebald, E., King, L., Edwards, M., Williams, J., III, Mundlos, S., Krakow, D. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ejhg.2012.197 publisherName Nature Publishing Group title A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression. mimNumber 601146 referenceNumber 6 publisherAbbreviation NPG pubmedID 22929025 source Europ. J. Hum. Genet. 21: 517-521, 2013. authors Dodd, A. W., Syddall, C. M., Loughlin, J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.32435 publisherName John Wiley & Sons, Inc. title Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia. mimNumber 601146 referenceNumber 7 publisherAbbreviation Wiley pubmedID 18629880 source Am. J. Med. Genet. 146A: 2116-2121, 2008. authors Douzgou, S., Lehmann, K., Mingarelli, R., Mundlos, S., Dallapiccola, B. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/ajmg.10777 publisherName John Wiley & Sons, Inc. title The mutational spectrum of brachydactyly type C. mimNumber 601146 referenceNumber 8 publisherAbbreviation Wiley pubmedID 12357473 source Am. J. Med. Genet. 112: 291-296, 2002. authors Everman, D. B., Bartels, C. F., Yang, Y., Yanamandra, N., Goodman, F. R., Mendoza-Londono, J. R., Savarirayan, R., White, S. M., Graham, J. M., Jr., Gale, R. P., Svarch, E., Newman, W. G., Kleckers, A. R., Francomano, C. A., Govindaiah, V., Singh, L., Morrison, S., Thomas, J. T., Warman, M. L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/ajmg.10501 publisherName John Wiley & Sons, Inc. title Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia. mimNumber 601146 referenceNumber 9 publisherAbbreviation Wiley pubmedID 12124730 source Am. J. Med. Genet. 111: 31-37, 2002. authors Faiyaz-Ul-Haque, M., Ahmad, W., Wahab, A., Haque, S., Azim, A. C., Zaidi, S. H. E., Teebi, A. S., Ahmad, M., Cohn, D. H., Siddique, T., Tsui, L.-C. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2002&volume=61&issue=6&spage=454 publisherName Blackwell Publishing title Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). mimNumber 601146 referenceNumber 10 publisherAbbreviation Blackwell pubmedID 12121354 source Clin. Genet. 61: 454-458, 2002. authors Faiyaz-Ul-Haque, M., Ahmad, W., Zaidi, S. H. E., Haque, S., Teebi, A. S., Ahmad, M., Cohn, D. H., Tsui, L. C. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ title Inherited brachydactyly and hypoplasia of the bones of the extremities. mimNumber 601146 referenceNumber 11 pubmedID 13953230 source Ann. Hum. Genet. 26: 201-212, 1963. authors Haws, D. 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W. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16014698 publisherName HighWire Press title A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2. mimNumber 601146 referenceNumber 14 publisherAbbreviation HighWire pubmedID 16014698 source J. Med. Genet. 43: 225-231, 2006. authors Kjaer, K. W., Eiberg, H., Hansen, L., van der Hagen, C. B., Rosendahl, K., Tommerup, N., Mundlos, S. pubmedImages false publisherUrl http://highwire.stanford.edu title A severe autosomal recessive acromesomelic dysplasia, the Hunter-Thompson type, and comparison with the Grebe type. mimNumber 601146 referenceNumber 15 pubmedID 2703235 source Hum. Genet. 81: 323-328, 1989. authors Langer, L. O., Jr., Cervenka, J., Camargo, M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(96)90257-8 publisherName Elsevier Science title Assignment of a new TGF-beta superfamily member, human cartilage-derived morphogenetic protein-1, to chromosome 20q11.2. mimNumber 601146 referenceNumber 16 publisherAbbreviation ES pubmedID 8661040 source Genomics 34: 150-151, 1996. authors Lin, K., Thomas, J. T., McBride, O. W., Luyten, F. P. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17656374 publisherName HighWire Press title A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. mimNumber 601146 referenceNumber 17 publisherAbbreviation HighWire pubmedID 17656374 source Hum. Molec. Genet. 16: 2366-2375, 2007. authors Masuya, H., Nishida, K., Furuichi, T., Toki, H., Nishimura, G., Kawabata, H., Yokoyama, H., Yoshida, A., Tominaga, S., Nagano, J., Shimizu, A., Wakana, S., Gondo, Y., Noda, T., Shiroishi, T., Ikegawa, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/2005 publisherName Nature Publishing Group title A functional polymorphism in the 5-prime UTR of GDF5 is associated with susceptibility to osteoarthritis. mimNumber 601146 referenceNumber 18 publisherAbbreviation NPG pubmedID 17384641 source Nature Genet. 39: 529-553, 2007. authors Miyamoto, Y., Mabuchi, A., Shi, D., Kubo, T., Takatori, Y., Saito, S., Fujioka, M., Sudo, A., Uchida, A., Yamamoto, S., Ozaki, K., Takigawa, M., Tanaka, T., Nakamura, Y., Jiang, Q., Ikegawa, S. pubmedImages false publisherUrl http://www.nature.com source Washington: Carnegie Inst. (pub.) 1919. Pp. 5-64. Note: Publ. 295. mimNumber 601146 authors Mohr, O. L., Wriedt, C. title A New Type of Hereditary Brachyphalangy in Man. referenceNumber 19 articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18203755 publisherName HighWire Press title Brachydactyly type A2 associated with a defect in proGDF5 processing. mimNumber 601146 referenceNumber 20 publisherAbbreviation HighWire pubmedID 18203755 source Hum. Molec. Genet. 17: 1222-1233, 2008. authors Ploger, F., Seemann, P., Schmidt-von Kegler, M., Lehmann, K., Seidel, J., Kjaer, K. W., Pohl, J., Mundlos, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/ng0997-18 publisherName Nature Publishing Group title Mutations in CDMP1 cause autosomal dominant brachydactyly type C. (Letter) mimNumber 601146 referenceNumber 21 publisherAbbreviation NPG pubmedID 9288091 source Nature Genet. 17: 18-19, 1997. authors Polinkovsky, A., Robin, N. H., Thomas, J. T., Irons, M., Lynn, A., Goodman, F. R., Reardon, W., Kant, S. G., Brunner, H. G., van der Burgt, I., Chitayat, D., McGaughran, J., Donnai, D., Luyten, F. P., Warman, M. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/(SICI)1096-8628(19970131)68:3<369::AID-AJMG23>3.0.CO;2-Q publisherName John Wiley & Sons, Inc. title Clinical and locus heterogeneity in brachydactyly type C. mimNumber 601146 referenceNumber 22 publisherAbbreviation Wiley pubmedID 9024575 source Am. J. Med. Genet. 68: 369-377, 1997. authors Robin, N. H., Gunay-Aygun, M., Polinkovsky, A., Warman, M. L., Morrison, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source J. Hered. 50: 81-84, 1959. mimNumber 601146 authors Runner, M. N. title Linkage of brachypodism: a new member of linkage group V of the house mouse. referenceNumber 23 articleUrl http://dx.doi.org/10.1038/ng.2772 publisherName Nature Publishing Group title BMP signaling controls muscle mass. mimNumber 601146 referenceNumber 24 publisherAbbreviation NPG pubmedID 24076600 source Nature Genet. 45: 1309-1318, 2013. authors Sartori, R., Schirwis, E., Blaauw, B., Bortolanza, S., Zhao, J., Enzo, E., Stantzou, A., Mouisel, E., Toniolo, L., Ferry, A., Stricker, S., Goldberg, A. L., Dupont, S., Piccolo, S., Amthor, H., Sandri, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1002/ajmg.a.10924 publisherName John Wiley & Sons, Inc. title Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. mimNumber 601146 referenceNumber 25 publisherAbbreviation Wiley pubmedID 12567410 source Am. J. Med. Genet. 117A: 136-142, 2003. authors Savarirayan, R., White, S. M., Goodman, F. R., Graham, J. M., Jr., Delatycki, M. B., Lachman, R. S., Rimoin, D. L., Everman, D. B., Warman, M. L. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1002/ajmg.a.20349 publisherName John Wiley & Sons, Inc. title Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1 mimNumber 601146 referenceNumber 26 publisherAbbreviation Wiley pubmedID 14735582 source Am. J. Med. Genet. 124A: 356-363, 2004. authors Schwabe, G. C., Turkmen, S., Leschik, G., Palanduz, S., Stover, B., Goecke, T. O., Mundlos, S. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1172/JCI25118 publisherName Journal of Clinical Investigation title Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. mimNumber 601146 referenceNumber 27 publisherAbbreviation JCI pubmedID 16127465 source J. Clin. Invest. 115: 2373-2381, 2005. authors Seemann, P., Schwappacher, R., Kjaer, K. W., Krakow, D., Lehmann, K., Dawson, K., Stricker, S., Pohl, J., Ploger, F., Staub, E., Nickel, J., Sebald, W., Knaus, P., Mundlos, S. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0012160602000222 publisherName Elsevier Science title Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. mimNumber 601146 referenceNumber 28 publisherAbbreviation ES pubmedID 12606286 source Dev. Biol. 254: 116-130, 2003. authors Settle, S. H., Jr., Rountree, R. B., Sinha, A., Thacker, A., Higgins, K., Kingsley, D. M. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/368639a0 publisherName Nature Publishing Group title Limb alterations in brachypodism mice due to mutations in a new member of the TGF-beta superfamily. mimNumber 601146 referenceNumber 29 publisherAbbreviation NPG pubmedID 8145850 source Nature 368: 639-643, 1994. authors Storm, E. E., Huynh, T. V., Copeland, N. G., Jenkins, N. A., Kingsley, D. M., Lee, S. J. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=9012517 publisherName HighWire Press title Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. mimNumber 601146 referenceNumber 30 publisherAbbreviation HighWire pubmedID 9012517 source Development 122: 3969-3979, 1996. authors Storm, E. E., Kingsley, D. M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.30969 publisherName John Wiley & Sons, Inc. title Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. mimNumber 601146 referenceNumber 31 publisherAbbreviation Wiley pubmedID 16222676 source Am. J. Med. Genet. 138A: 379-383, 2005. authors Szczaluba, K., Hilbert, K., Obersztyn, E., Zabel, B., Mazurczak, T., Kozlowski, K. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng0997-58 publisherName Nature Publishing Group title Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. mimNumber 601146 referenceNumber 32 publisherAbbreviation NPG pubmedID 9288098 source Nature Genet. 17: 58-64, 1997. authors Thomas, J. T., Kilpatrick, M. W., Lin, K., Erlacher, L., Lembessis, P., Costa, T., Tsipouras, P., Luyten, F. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/ng0396-315 publisherName Nature Publishing Group title A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. mimNumber 601146 referenceNumber 33 publisherAbbreviation NPG pubmedID 8589725 source Nature Genet. 12: 315-317, 1996. authors Thomas, J. T., Lin, K., Nandedkar, M., Camargo, M., Cervenka, J., Luyten, F. P. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/86342 publisherName Nature Publishing Group title A CD14-independent LPS receptor cluster. mimNumber 601146 referenceNumber 34 publisherAbbreviation NPG pubmedID 11276205 source Nature Immun. 2: 338-345, 2001. Note: Erratum: Nature Immun. 2: 658 only, 2001. authors Triantafilou, K., Triantafilou, M., Dedrick, R. L. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.jcb.org/cgi/pmidlookup?view=long&pmid=9885252 publisherName HighWire Press title Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. mimNumber 601146 referenceNumber 35 publisherAbbreviation HighWire pubmedID 9885252 source J. Cell Biol. 144: 161-173, 1999. authors Tsumaki, N., Tanaka, K., Arikawa-Hirasawa, E., Nakase, T., Kimura, T., Thomas, J. T., Ochi, T., Luyten, F. P., Yamada, Y. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ajmg.a.31372 publisherName John Wiley & Sons, Inc. title A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. mimNumber 601146 referenceNumber 36 publisherAbbreviation Wiley pubmedID 16892395 source Am. J. Med. Genet. 140A: 1846-1853, 2006. authors Wang, X., Xiao, F., Yang, Q., Liang, B., Tang, Z., Jiang, L., Zhu, Q., Chang, W., Jiang, J., Jiang, C., Ren, X., Liu, J.-Y., Wang, Q. K., Liu, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. mimNumber 601146 referenceNumber 37 pubmedID 18283415 source J. Hum. Genet. 53: 368-374, 2008. authors Yang, W., Cao, L., Liu, W., Jiang, L., Sun, M., Zhang, D., Wang, S., Lo, W. H. Y., Luo, Y., Zhang, X. pubmedImages false externalLinks mgiIDs MGI:95688 mgiHumanDisease false ncbiReferenceSequences 574956984 refSeqAccessionIDs NG_008076.1 dermAtlas false hprdIDs 03092 swissProtIDs P43026 zfinIDs ZDB-GENE-990415-39 uniGenes Hs.1573 gtr true cmgGene false ensemblIDs ENSG00000125965,ENST00000374369 umlsIDs C1333666 genbankNucleotideSequences 84798797,313882485,114211791,118140160,511788365,23291439,326205372,3715254,60496340,218087664,440546322,600731,118629258,148173003,240149874,2298567,6463691,22749746,11345543,671524,218049681,223970729,85360038,74230043,190691492,160736875 geneTests true approvedGeneSymbols GDF5 geneIDs 8200 proteinSequences 84798798,313882486,7671666,118140161,326205373,60496341,218087665,611435007,3715255,600732,118629259,114211792,240149875,119596614,119596615,22749747,2298568,218049682,6463692,671525,85360039,223970730,160736876,190691493,20141384 nextGxDx true

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entry contributors Marla J. F. O'Neill - updated : 8/25/2011 Marla J. F. O'Neill - updated : 6/22/2010 Marla J. F. O'Neill - updated : 2/19/2009 Matthew B. Gross - reorganized : 11/6/2008 Matthew B. Gross - updated : 11/6/2008 Patricia A. Hartz - updated : 10/29/2008 Marla J. F. O'Neill - updated : 8/30/2006 Jane Kelly - updated : 8/1/2005 Marla J. F. O'Neill - updated : 11/8/2004 Victor A. McKusick - updated : 1/22/2003 Michael B. Petersen - updated : 1/15/2003 John A. Phillips, III - updated : 7/30/2002 John A. Phillips, III - updated : 7/29/2002 John A. Phillips, III - updated : 7/26/2002 Victor A. McKusick - updated : 4/8/2002 Victor A. McKusick - updated : 1/25/2002 John A. Phillips, III - updated : 10/1/2001 Victor A. McKusick - updated : 6/20/2001 Victor A. McKusick - updated : 5/18/2001 Ada Hamosh - updated : 5/11/1999 John A. Phillips, III - updated : 1/7/1999 Victor A. McKusick - updated : 8/26/1998 Victor A. McKusick - updated : 7/13/1998 Victor A. McKusick - updated : 10/14/1997 Michael J. Wright - updated : 9/25/1997 John A. Phillips, III - updated : 9/12/1997 Victor A. McKusick - updated : 8/19/1997 Victor A. McKusick - updated : 2/6/1997 Moyra Smith - updated : 11/20/1996 Moyra Smith - updated : 11/20/1996 Alan F. Scott - updated : 2/27/1996 prefix + titles alternativeTitles PON;; PARAOXONASE, PLASMA;; ARYLESTERASE;; ESTERASE A; ESA includedTitles PON1 ENZYME ACTIVITY, VARIATION IN, INCLUDED;; ORGANOPHOSPHATE POISONING, SUSCEPTIBILITY TO, INCLUDED;; CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;; CORONARY ARTERY SPASM 2, SUSCEPTIBILITY TO, INCLUDED preferredTitle PARAOXONASE 1; PON1 allelicVariantExists true geneMap geneSymbols PON1, PON, ESA, MVCD5 sequenceID 5806 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 168820 phenotypeInheritance None phenotype {Coronary artery disease, susceptibility to} phenotypeMappingKey 3 mimNumber 168820 phenotypeInheritance None phenotype {Coronary artery spasm 2, susceptibility to phenotypeMimNumber 612633 mimNumber 168820 phenotypeInheritance None phenotypicSeriesMimNumber 603933 phenotypeMappingKey 3 phenotype {Microvascular complications of diabetes 5} phenotypeMappingKey 3 mimNumber 168820 phenotypeInheritance None phenotype {Organophosphate poisoning, sensitivity to} chromosomeLocationStart 94927668 chromosomeSort 364 chromosomeSymbol 7 mimNumber 168820 geneInheritance Autosomal dominant confidence C mappingMethod F, Fd, REc geneName Paraoxonase-1 mouseMgiID MGI:103295 mouseGeneSymbol Pon1 computedCytoLocation 7q21.3 cytoLocation 7q21.3 transcript uc003uns.3 chromosomeLocationEnd 94953883 chromosome 7 clinicalSynopsisExists true allelicVariantList allelicVariant status live name PON1 ENZYME ACTIVITY, VARIATION IN dbSnps rs662 text {27:Humbert et al. (1993)} found that arginine at position 192 of PON1 specifies high-activity plasma paraoxonase, whereas glutamine at this position specifies a low-activity variant. They showed that allele-specific probes or restriction enzyme analysis of amplified DNA could be used for genotyping of individuals. This polymorphism is also referred to as GLN191ARG. {1:Adkins et al. (1993)} also demonstrated that glutamine or arginine at amino acid 191 determines the A and B allozymes, respectively, of PON1. {49:Serrato and Marian (1995)}, who referred to the gln192-to-arg (Q192R) polymorphism as the A/G polymorphism or the A/B polymorphism, demonstrated a relationship to coronary artery disease. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with the A genotype have a lower enzymatic activity than those with the B genotype. {49:Serrato and Marian (1995)} determined the genotypes in 223 patients with angiographically documented coronary artery disease and in 247 individuals in the general population. The distribution of genotypes was in Hardy-Weinberg equilibrium in both groups. Genotypes A and B were present in 49% and 11% of control individuals and in 30% and 18% of patients with coronary artery disease, respectively (p = 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no difference in the distribution of PON genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for coronary artery disease as compared with corresponding subgroups. {2:Antikainen et al. (1996)} referred to this polymorphism as gln191 to arg (Q191R). In Finns they were unable to confirm an association with the risk of coronary artery disease. The most common genotype found in both 380 well-characterized CAD patients and 169 controls was AA (gln/gln). The frequency of the A allele was 0.74 in both patients and controls. The genotype distributions of the 2 groups did not differ and were similar to those reported earlier in other caucasoid populations. {42:Odawara et al. (1997)} performed an association study of the arg192 polymorphism with coronary heart disease (CHD) in Japanese noninsulin-dependent diabetes mellitus (NIDDM; {125853}) subjects. They genotyped 164 NIDDM patients (42 with and 122 without CHD). Other known risk factors for CHD were matched between the 2 groups. AB + BB isoforms were detected in 41 of 42 NIDDM patients with CHD. The proportion of B allele carriers (AB + BB) was significantly higher than that of AA carriers among NIDDM patients with CHD compared to those without CHD (chi square = 7.68, p = 0.003). Multivariate logistic regression analyses showed an increased odds ratio (8.8; CI, 1.1-69) in B allele carriers, while odds ratios of other risk factors remained between 1.0 and 1.9. The authors concluded that Japanese NIDDM patients who are carriers of the B allele of the gln192-to-arg polymorphism have an increased risk for developing CHD independent of other known risk factors for CHD. The arg192 isoform of paraoxonase hydrolyzes paraoxon more rapidly than the gln192 isoform. However, with respect to hydrolysis of toxic nerve agents, such as sarin, the arg192 isoform displays a lower activity than the other isoform. {57:Yamasaki et al. (1997)} found that the arg192 allele is more common in the Japanese (allele frequency, 0.66) than in people of other races (range, 0.24 to 0.31). In Japanese, 41.4% of subjects were homozygous for the arg192 allele, which shows a very low hydrolysis activity for sarin. Thus, there seems to be a racial difference in vulnerability to toxic nerve agents, such as sarin. The dominance of the arg192 allele in the Japanese population probably worsened the tragedy of March 1995 in the Tokyo subway. {26:Heinecke and Lusis (1998)} reviewed the results of previous studies of the PON1 Q192R polymorphism in CHD and raised the question of whether these PON polymorphisms support the oxidative damage hypothesis of atherosclerosis. {44:Paolisso et al. (2001)} investigated the relationship between a PON1 polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridemia as a prooxidant factor. In 101 healthy subjects the response to flow-induced vasodilation was measured before and after Intralipid infusion. In the same subjects the A/B PON1 polymorphism was genotyped. The frequency was 0.545 for the AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline all genotype groups had similar increases in brachial artery diameter and flow. After Intralipid infusion, subjects sharing the BB genotype had a significant decrease versus baseline values in changes in brachial artery diameter, but not in flow. In a subgroup of 55 subjects distributed along the 3 PON1 genotypes the same study protocol was repeated by buccal nitroglycerine administration to study the endothelium-independent vasodilation. Again, subjects with the BB genotype had the worse vasodilation. The authors concluded that transient hypertriglyceridemia decreases vascular reactivity more in subjects with the PON1 BB genotype than in those with the other PON1 genotypes. {29:Ito et al. (2002)} found that the incidence of the PON1 192R allele was significantly higher in a cohort of 214 Japanese patients with coronary spasm than in 212 control subjects. They speculated that the high frequency of the PON1 arg192 allele may be related to the higher prevalence of coronary spasm among Japanese than among Caucasians. They also noted that cigarette smoking reduces serum PON1 activity in patients with coronary artery disease, and that cigarette smoking is highly prevalent in the Japanese. PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. {9:Cherry et al. (2002)} studied PON1 polymorphisms in 175 farmers with ill health that they attributed to sheep dip and 234 other farmers nominated by the ill farmers and thought to be in good health despite having also dipped sheep. They calculated odds ratios for the Q192R and L55M ({168820.0002}) polymorphisms, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least 1 R allele at position 192 (odds ratio 1.93), both alleles of type LL (odds ratio 1.70) at position 55, and to have diazoxonase activity below normal median (odds ratio 1.77). The results supported the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep. {5:Bonafe et al. (2002)} examined the Q192R polymorphism in 308 Italian unrelated centenarians and 579 Italian individuals aged 20 to 65 years. The percentage of carriers of the R192 allele was significantly higher in centenarians than in young people (0.539 vs 0.447, p = 0.011). No significant difference between centenarians and young individuals was observed for the PON1 L55M polymorphism ({168820.0002}). The authors proposed that the R192 allele decreases mortality in carriers, but that the effect of PON1 variability on the overall population mortality is rather slight. The findings suggested that PON1 is one of the genes affecting the individual adaptive capacity and is therefore one of the genes affecting rate and quality of aging ({152430}). In a longitudinal study of survival involving 1,932 Danish individuals, {10:Christiansen et al. (2004)} found that women homozygous for the R192 allele had a poorer survival rate compared to Q192 homozygotes (hazard ratio, 1.38; p = 0.04). An independent sample of 541 Danish individuals confirmed the findings for R192 homozygous women, with a hazard ratio of 1.38 (p = 0.09). Combining the 2 samples did not change the risk estimate, but increased the statistical significance (p = 0.008). Using self-reported data on ischemic heart disease, the authors found only a nonsignificant trend of R192 homozygosity in women being a risk factor. {10:Christiansen et al. (2004)} concluded that PON1 R192 homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to the development of CHD. Using a validated microsomal expression system of metabolizing enzymes, {6:Bouman et al. (2011)} identified PON1 as the crucial enzyme for the bioactivation of the antiplatelet drug clopidogrel, with the common Q192R polymorphism determining the rate of active metabolite formation. A case-cohort study of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy revealed that Q192 homozygotes were more likely to undergo stent thrombosis than patients with the RR192 or QR192 genotypes (odds ratio, 3.6; p = 0.0003). In addition, PON1 QQ192 homozygotes showed a considerably higher risk than RR192 homozygotes of lower PON1 plasma activity, lower plasma concentrations of active metabolite, and lower platelet inhibition. mutations PON1, GLN192ARG number 1 alternativeNames CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;; CORONARY ARTERY SPASM 2, SUSCEPTIBILITY TO, INCLUDED clinvarAccessions RCV000014740;;1;;;RCV000133464;;1;;;RCV000014739;;1 status live name PON1 ENZYME ACTIVITY, VARIATION IN dbSnps rs854560 text This polymorphism was originally designated MET54LEU (M54L; {22:Garin et al., 1997}) and has also been designated MET55LEU (M55L; e.g., {31,30:Kao et al., 1998, 2002}). It is referred to here as LEU55MET (L55M) because {7:Brophy et al. (2001)} noted that leucine is the more frequent amino acid at position 55 (or 54, depending on the numbering system). {22:Garin et al. (1997)} investigated this polymorphism in 408 diabetic patients with or without vascular disease. There were highly significant differences in plasma concentrations and activities of paraoxonase between genotypes defined by the met54-to-leu polymorphism. On the other hand, the arg191 variant ({168820.0001}) had little impact on paraoxonase concentration. Homozygosity for the leu54 allele was an independent risk factor for cardiovascular disease. A linkage disequilibrium was apparent between the mutations giving rise to leu54 and arg191. {22:Garin et al. (1997)} stated that their study underlined the fact that susceptibility to cardiovascular disease correlated with high-activity paraoxonase alleles. The M54L polymorphism appeared to be of central importance to paraoxonase function by virtue of its association with modulated concentrations. Linkage disequilibrium could explain the association between both the leu54 and the arg191 polymorphisms and CVD. {7:Brophy et al. (2001)} presented evidence that the L55M effect of lowered activity is not due primarily to the amino acid change itself but to linkage disequilibrium with the -108 regulatory region polymorphism ({168820.0003}). The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1 expression levels, which was much greater than that attributable to other PON1 polymorphisms. {14:Deakin et al. (2002)} analyzed glucose metabolism as a function of PON1 polymorphisms in young healthy nondiabetic men from families with premature coronary heart disease (CHD) and matched controls. The L55M PON1 polymorphism was independently associated with the glucose response to an oral glucose tolerance test. LL homozygotes had significantly impaired glucose disposal (p = 0.0007) compared with LM and MM genotypes. It was particularly marked for subjects from high CHD risk families and differentiated them from matched controls (p = 0.049). The area under the glucose curve (p = 0.0036) and the time to peak glucose value (p = 0.026) were significantly higher in the LL carriers, whereas the insulin response was slower (p = 0.013). The results showed that an association exists between PON1 gene polymorphisms and glucose metabolism. The authors also concluded that the L55M-glucose interaction differentiated offspring of high CHD risk families, suggesting that it may be of particular relevance for vascular disease and possibly other diabetic complications. {4:Barbieri et al. (2002)} investigated association of the M54L polymorphism with the degree of insulin resistance (IR) in 213 healthy subjects by the homeostasis model assessment. The frequency was 0.366 for the LL genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype. Comparing the 3 genotype groups, LL genotype had the more severe degree of IR. Subjects carrying the LL genotype were associated with the IR syndrome picture more than individuals carrying the M allele because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high density lipoprotein cholesterol. In a multivariate stepwise regression analysis, LL genotype was a significant predictor of IR, independent of age, sex, body mass index, fasting plasma triglycerides, and high density lipoprotein cholesterol. The authors concluded that the presence of LL PON genotype is associated with a more severe degree of IR. Thus, IR might be the possible missing link between the M54L polymorphism and the increased cardiovascular risk. {31:Kao et al. (1998)} investigated the potential significance of these PON1 polymorphisms in the pathogenesis of diabetic retinopathy in IDDM (MVCD5; {612633}). They analyzed samples from 80 patients with diabetic retinopathy and 119 controls. The allelic frequency of the leu54 (L) polymorphism was significantly higher in the group with retinopathy than in the group without retinopathy (73% vs 57%, p less than 0.001). {31:Kao et al. (1998)} concluded that the genotype L/L was strongly associated with the development of diabetic retinopathy (p less than 0.001), but a similar association was not found with the arg192 polymorphism. {30:Kao et al. (2002)} analyzed the M54L PON1 polymorphism in 372 adolescents with type 1 diabetes ({222100}) and confirmed increased susceptibility to diabetic retinopathy with the leu/leu genotype (odds ratio, 3.4; p less than 0.0001) independent of age, duration of disease, and cholesterol. mutations PON1, LEU55MET number 2 alternativeNames CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED;; MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 5, INCLUDED clinvarAccessions RCV000133465;;1;;;RCV000014742;;1;;;RCV000014743;;1 status live name PON1 ENZYME ACTIVITY, VARIATION IN dbSnps rs705379 text {7:Brophy et al. (2001)} concluded that the -108C/T polymorphism in the 5-prime regulatory region of the PON1 gene accounts for 22.8% of the observed variability in PON1 expression levels, which is much greater than that attributable to other PON1 polymorphisms. mutations PON1, -108C-T number 3 clinvarAccessions RCV000133466;;1 geneMapExists true editHistory terry : 09/14/2012 carol : 12/22/2011 carol : 8/25/2011 terry : 8/25/2011 wwang : 6/28/2010 terry : 6/22/2010 wwang : 1/13/2010 ckniffin : 12/29/2009 ckniffin : 7/30/2009 alopez : 4/2/2009 carol : 2/23/2009 terry : 2/19/2009 alopez : 12/16/2008 mgross : 11/6/2008 mgross : 11/6/2008 mgross : 11/6/2008 mgross : 11/6/2008 terry : 10/29/2008 carol : 10/10/2007 alopez : 3/27/2007 carol : 9/5/2006 terry : 8/30/2006 alopez : 8/1/2005 terry : 2/18/2005 tkritzer : 11/11/2004 tkritzer : 11/8/2004 carol : 7/6/2004 joanna : 3/17/2004 tkritzer : 1/31/2003 tkritzer : 1/22/2003 terry : 1/22/2003 cwells : 1/15/2003 tkritzer : 7/31/2002 tkritzer : 7/30/2002 tkritzer : 7/29/2002 tkritzer : 7/26/2002 cwells : 4/19/2002 cwells : 4/15/2002 terry : 4/8/2002 carol : 2/21/2002 carol : 2/15/2002 mcapotos : 2/6/2002 terry : 1/25/2002 alopez : 10/1/2001 carol : 10/1/2001 mcapotos : 6/26/2001 mcapotos : 6/21/2001 terry : 6/20/2001 mcapotos : 5/25/2001 terry : 5/18/2001 carol : 5/20/1999 alopez : 5/14/1999 terry : 5/11/1999 alopez : 4/7/1999 alopez : 1/7/1999 carol : 8/27/1998 terry : 8/26/1998 alopez : 7/15/1998 terry : 7/13/1998 alopez : 3/16/1998 alopez : 11/19/1997 alopez : 11/11/1997 alopez : 11/11/1997 alopez : 11/6/1997 jenny : 10/21/1997 terry : 10/14/1997 dholmes : 10/2/1997 dholmes : 10/1/1997 dholmes : 9/22/1997 terry : 8/19/1997 mark : 3/16/1997 terry : 2/6/1997 terry : 1/24/1997 jamie : 11/22/1996 mark : 11/20/1996 mark : 11/20/1996 mark : 10/16/1996 terry : 10/9/1996 terry : 9/10/1996 terry : 8/23/1996 terry : 4/17/1996 mark : 2/27/1996 mark : 1/27/1996 terry : 1/19/1996 mimadm : 1/14/1995 davew : 7/14/1994 warfield : 3/3/1994 carol : 1/28/1993 carol : 11/12/1992 carol : 11/9/1992 dateUpdated Fri, 14 Sep 2012 03:00:00 EDT referenceList reference title Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A and B allozymes. mimNumber 168820 referenceNumber 1 pubmedID 7916578 source Am. J. Hum. Genet. 52: 598-608, 1993. authors Adkins, S., Gan, K. N., Mody, M., La Du, B. N. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI118869 publisherName Journal of Clinical Investigation title The gln-arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns. mimNumber 168820 referenceNumber 2 publisherAbbreviation JCI pubmedID 8770857 source J. Clin. Invest. 98: 883-885, 1996. authors Antikainen, M., Murtomaki, S., Syvanne, M., Pahlman, R., Tahvanainen, E., Jauhiainen, M., Frick, M. H., Ehnholm, C. pubmedImages false publisherUrl http://www.jci.org articleUrl http://linkinghub.elsevier.com/retrieve/pii/0304-4165(66)90195-4 publisherName Elsevier Science title A genetically controlled esterase in rat plasma. mimNumber 168820 referenceNumber 3 publisherAbbreviation ES pubmedID 5968902 source Biochim. Biophys. Acta 124: 323-331, 1966. authors Augustinsson, K.-B., Henricson, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11788650 publisherName HighWire Press title LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects. mimNumber 168820 referenceNumber 4 publisherAbbreviation HighWire pubmedID 11788650 source J. Clin. Endocr. Metab. 87: 222-225, 2002. authors Barbieri, M., Bonafe, M., Marfella, R., Ragno, E., Giugliano, D., Franceschi, C., Paolisso, G. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1038/sj.ejhg.5200806 publisherName Nature Publishing Group title Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of arg192 allele in centenarians. mimNumber 168820 referenceNumber 5 publisherAbbreviation NPG pubmedID 12082503 source Europ. J. Hum. Genet. 10: 292-296, 2002. authors Bonafe, M., Marchegiani, F., Cardelli, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Pieri, C., Marra, M., Antonicelli, R., Troiano, L., Gueresi, P., Passeri, G., Berardelli, M., Paolisso, G., Barbieri, M., Tesai, S., Lisa, R., De Benedictis, G., Franceschi, C. pubmedImages false publisherUrl http://www.nature.com articleUrl http://dx.doi.org/10.1038/nm.2281 publisherName Nature Publishing Group title Paraoxonase-1 is a major determinant of clopidogrel efficacy. mimNumber 168820 referenceNumber 6 publisherAbbreviation NPG pubmedID 21170047 source Nature Med. 17: 110-116, 2011. Note: Erratum: Nature Med. 17: 1153 only, 2011. authors Bouman, H. J., Schomig, E., van Werkum, J. W., Velder, J., Hackeng, C. M., Hirschhauser, C., Waldmann, C., Schmalz, H.-G., ten Berg, J. M., Taubert, D. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61053-2 publisherName Elsevier Science title Effects of 5-prime regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. mimNumber 168820 referenceNumber 7 publisherAbbreviation ES pubmedID 11335891 source Am. J. Hum. Genet. 68: 1428-1436, 2001. authors Brophy, V. H., Jampsa, R. L., Clendenning, J. B., McKinstry, L. A., Jarvik, G. P., Furlong, C. E. pubmedImages true publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60500-X publisherName Elsevier Science title Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. mimNumber 168820 referenceNumber 8 publisherAbbreviation ES pubmedID 12454802 source Am. J. Hum. Genet. 72: 13-22, 2003. authors Chen, Q., Reis, S. E., Kammerer, C. M., McNamara, D. M., Holubkov, R., Sharaf, B. L., Sopko, G., Pauly, D. F., Merz, C. N. B., Kamboh, M. I. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140673602078479 publisherName Elsevier Science title Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip. mimNumber 168820 referenceNumber 9 publisherAbbreviation ES pubmedID 11888590 source Lancet 359: 763-764, 2002. authors Cherry, N., Mackness, M., Durrington, P., Povey, A., Dippnall, M., Smith, T., Mackness, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/sj.ejhg.5201235 publisherName Nature Publishing Group title Paraoxonase 1 polymorphisms and survival. mimNumber 168820 referenceNumber 10 publisherAbbreviation NPG pubmedID 15241482 source Europ. J. Hum. Genet. 12: 843-847, 2004. authors Christiansen, L., Bathum, L., Frederiksen, H., Christensen, K. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(96)90401-2 publisherName Elsevier Science title Structural organization of the human PON1 gene. mimNumber 168820 referenceNumber 11 publisherAbbreviation ES pubmedID 8812495 source Genomics 35: 586-589, 1996. authors Clendenning, J. B., Humbert, R., Green, E. D., Wood, C., Traver, D., Furlong, C. E. pubmedImages false publisherUrl http://www.elsevier.com/ title A preliminary interpretation of the esterase isozymes of human tissues. mimNumber 168820 referenceNumber 12 pubmedID 1180483 source Ann. Hum. Genet. 39: 1-20, 1975. authors Coates, P. M., Mestriner, M. A., Hopkinson, D. A. pubmedImages false title The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. mimNumber 168820 referenceNumber 13 pubmedID 8896566 source Nature Genet. 14: 334-336, 1996. authors Davies, H. G., Richter, R. J., Keifer, M., Broomfield, C. A., Sowalla, J., Furlong, C. E. pubmedImages false articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11889198 publisherName HighWire Press title Paraoxonase-1 L55M polymorphism is associated with an abnormal oral glucose tolerance test and differentiates high risk coronary disease families. mimNumber 168820 referenceNumber 14 publisherAbbreviation HighWire pubmedID 11889198 source J. Clin. Endocr. Metab. 87: 1268-1273, 2002. authors Deakin, S., Leviev, I., Nicaud, V., Meynet, M.-C. B., Tiret, L., James, R. W. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.jlr.org/cgi/pmidlookup?view=long&pmid=15772423 publisherName HighWire Press title Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. mimNumber 168820 referenceNumber 15 publisherAbbreviation HighWire pubmedID 15772423 source J. Lipid Res. 46: 1239-1247, 2005. authors Draganov, D. I., Teiber, J. F., Speelman, A., Osawa, Y., Sunahara, R., La Du, B. N. pubmedImages false publisherUrl http://highwire.stanford.edu title The human serum paraoxonase polymorphism: identification of phenotypes by their response to salts. mimNumber 168820 referenceNumber 16 pubmedID 6301268 source Am. J. Hum. Genet. 35: 214-227, 1983. authors Eckerson, H. W., Romson, J., Wyte, C., La Du, B. N. pubmedImages false title The human serum paraoxonase/arylesterase polymorphism. mimNumber 168820 referenceNumber 17 pubmedID 6316781 source Am. J. Hum. Genet. 35: 1126-1136, 1983. authors Eckerson, H. W., Wyte, C. M., La Du, B. N. pubmedImages false source Cytogenet. Cell Genet. 25: 150, 1979. mimNumber 168820 authors Eiberg, H., Mohr, J. title Linkage relations of the paraoxonase polymorphism with 43 marker systems. (Abstract) referenceNumber 18 title Linkage relationships of paraoxonase (PON) with other markers: indication of PON-cystic fibrosis synteny. mimNumber 168820 referenceNumber 19 pubmedID 2998653 source Clin. Genet. 28: 265-271, 1985. authors Eiberg, H., Mohr, J., Schmiegelow, K., Nielsen, L. S., Williamson, R. pubmedImages false title Purification of rabbit and human serum paraoxonase. mimNumber 168820 referenceNumber 20 pubmedID 1718413 source Biochemistry 30: 10133-10140, 1991. authors Furlong, C. E., Richter, R. J., Chapline, C., Crabb, J. W. pubmedImages false title Role of genetic polymorphism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. mimNumber 168820 referenceNumber 21 pubmedID 2458038 source Am. J. Hum. Genet. 43: 230-238, 1988. authors Furlong, C. E., Richter, R. J., Seidel, S. L., Motulsky, A. G. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI119134 publisherName Journal of Clinical Investigation title Paraoxonase polymorphism met-leu54 is associated with modified serum concentrations of the enzyme: a possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. mimNumber 168820 referenceNumber 22 publisherAbbreviation JCI pubmedID 9011577 source J. Clin. Invest. 99: 62-66, 1997. authors Garin, M.-C. B., James, R. W., Dussoix, P., Blanche, H., Passa, P., Froguel, P., Ruiz, J. pubmedImages false publisherUrl http://www.jci.org source Hum. Genet. 45 (suppl. 1): 65-68, 1978. mimNumber 168820 authors Geldmacher-von Mallinckrodt, M. title Polymorphism of human serum paraoxonase. referenceNumber 23 title Genetisch determinierter Polymorphismus de menschlichen Serum-Paroxonase (E.C.3.1.1.2). mimNumber 168820 referenceNumber 24 pubmedID 4694515 source Humangenetik 17: 331-335, 1973. authors Geldmacher-von Mallinckrodt, M., Lindorft, H. H., Petenyi, M., Flugel, M., Fischer, T., Hiller, T. pubmedImages false title Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence. mimNumber 168820 referenceNumber 25 pubmedID 1657140 source Biochemistry 30: 10141-10149, 1991. authors Hassett, C., Richter, R. J., Humbert, R., Chapline, C., Crabb, J. W., Omiecinski, C. J., Furlong, C. E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60117-7 publisherName Elsevier Science title Paraoxonase-gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis? (Letter) mimNumber 168820 referenceNumber 26 publisherAbbreviation ES pubmedID 9443884 source Am. J. Hum. Genet. 62: 20-24, 1998. authors Heinecke, J. W., Lusis, A. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng0193-73 publisherName Nature Publishing Group title The molecular basis of the human serum paraoxonase activity polymorphism. mimNumber 168820 referenceNumber 27 publisherAbbreviation NPG pubmedID 8098250 source Nature Genet. 3: 73-76, 1993. authors Humbert, R., Adler, D. A., Disteche, C. M., Hassett, C., Omiecinski, C. J., Furlong, C. E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0002939401009758 publisherName Elsevier Science title Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration. mimNumber 168820 referenceNumber 28 publisherAbbreviation ES pubmedID 11476678 source Am. J. Ophthal. 132: 191-195, 2001. authors Ikeda, T., Obayashi, H., Hasegawa, G., Nakamura, N., Yoshikawa, T., Imamura, Y., Koizumi, K., Kinoshita, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s00439-001-0654-6 publisherName Springer title Paraoxonase gene gln192-to-arg (Q192R) polymorphism is associated with coronary artery spasm. mimNumber 168820 referenceNumber 29 publisherAbbreviation Springer pubmedID 11810302 source Hum. Genet. 110: 89-94, 2002. authors Ito, T., Yasue, H., Yoshimura, M., Nakamura, S., Nakayama, M., Shimasaki, Y., Harada, E., Mizuno, Y., Kawano, H., Ogawa, H. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0742-3071&date=2002&volume=19&issue=3&spage=212 publisherName Blackwell Publishing title Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes. mimNumber 168820 referenceNumber 30 publisherAbbreviation Blackwell pubmedID 11918623 source Diabet. Med. 19: 212-215, 2002. authors Kao, Y., Donaghue, K. C., Chan, A., Bennetts, B. H., Knight, J., Silink, M. pubmedImages false publisherUrl http://www.blackwellpublishing.com/ articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9661650 publisherName HighWire Press title A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. mimNumber 168820 referenceNumber 31 publisherAbbreviation HighWire pubmedID 9661650 source J. Clin. Endocr. Metab. 83: 2589-2592, 1998. authors Kao, Y.-L., Donaghue, K., Chan, A., Knight, J., Silink, M. pubmedImages false publisherUrl http://highwire.stanford.edu title The human serum paraoxonase/arylesterase polymorphism. (Editorial) mimNumber 168820 referenceNumber 32 pubmedID 2843045 source Am. J. Hum. Genet. 43: 227-229, 1988. authors La Du, B. N. pubmedImages false source Toxic. Lett. 76: 219-226, 1995. mimNumber 168820 authors Li, W.-F., Furlong, C. E., Costa, L. G. title Paraoxonase protects against chlorpyrifos toxicity in mice. referenceNumber 33 title Paraoxonase (Pon1) gene in mice: sequencing, chromosomal localization and developmental expression. mimNumber 168820 referenceNumber 34 pubmedID 9170151 source Pharmacogenetics 7: 137-144, 1997. authors Li, W.-F., Matthews, C., Disteche, C. M., Costa, L. G., Furlong, C. E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1046-5928(05)00258-5 publisherName Elsevier Science title Cloning, purification, and refolding of human paraoxonase-3 expressed in Escherichia coli and its characterization. mimNumber 168820 referenceNumber 35 publisherAbbreviation ES pubmedID 16139510 source Protein Expression and Purification 46: 92-99, 2006. authors Lu, H., Zhu, J., Zang, Y., Ze, Y., Qin, J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(98)00064-7 publisherName Elsevier Science title Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. mimNumber 168820 referenceNumber 36 publisherAbbreviation ES pubmedID 9506841 source FEBS Lett. 423: 57-60, 1998. authors Mackness, B., Mackness, M. I., Arrol, S., Turkie, W., Durrington, P. N. pubmedImages false publisherUrl http://www.elsevier.com/ title Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. mimNumber 168820 referenceNumber 37 pubmedID 9714608 source Gene 213: 149-157, 1998. authors Mochizuki, H., Scherer, S. W., Xi, T., Nickle, D. C., Majer, M., Huizenga, J. J., Tsui, L.-C., Prochazka, M. pubmedImages false title Plasma paraoxonase polymorphism: a new enzyme assay, population, family, biochemical, and linkage studies. mimNumber 168820 referenceNumber 38 pubmedID 6305189 source Am. J. Hum. Genet. 35: 393-408, 1983. authors Mueller, R. F., Hornung, S., Furlong, C. E., Anderson, J., Giblett, E. R., Motulsky, A. G. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI119369 publisherName Journal of Clinical Investigation title Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. mimNumber 168820 referenceNumber 39 publisherAbbreviation JCI pubmedID 9109446 source J. Clin. Invest. 99: 2005-2019, 1997. Note: Erratum: J. Clin. Invest. 99: 3043 only, 1997. authors Navab, M., Hama-Levy, S., Van Lenten, B. J., Fonarow, G. C., Cardinez, C. J., Castellani, L. W., Brennan, M.-L., Lusis, A. J., Fogelman, A. M., La Du, B. N. pubmedImages false publisherUrl http://www.jci.org title Genetic studies of the Macushi and Wapishana Indians. I. Rare genetic variants and a 'private polymorphism' of esterase A. mimNumber 168820 referenceNumber 40 pubmedID 870412 source Hum. Genet. 36: 81-108, 1977. authors Neel, J. V., Tanis, R. J., Migliazza, E. C., Spielman, R. S., Salzano, F. M., Oliver, W. J., Morrow, M., Bachofer, S. pubmedImages false title Number of loci responsible for the inheritance of high and low activity of paraoxonase. mimNumber 168820 referenceNumber 41 pubmedID 3009059 source Clin. Genet. 29: 216-221, 1986. authors Nielsen, A., Eiberg, H., Mohr, J. pubmedImages false articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9215303 publisherName HighWire Press title Paraoxonase polymorphism Gln192-Arg is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus. mimNumber 168820 referenceNumber 42 publisherAbbreviation HighWire pubmedID 9215303 source J. Clin. Endocr. Metab. 82: 2257-2260, 1997. authors Odawara, M., Tachi, Y., Yamashita, K. pubmedImages false publisherUrl http://highwire.stanford.edu title Paraoxon hydrolysis in human serum mediated by a genetically variable arylesterase and albumin. mimNumber 168820 referenceNumber 43 pubmedID 6324579 source Am. J. Hum. Genet. 36: 295-305, 1984. authors Ortigoza-Ferado, J., Richter, R. J., Hornung, S. K., Motulsky, A. G., Furlong, C. E. pubmedImages false articleUrl http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11238489 publisherName HighWire Press title The BB-paraoxonase genotype is associated with impaired brachial reactivity after acute hypertriglyceridemia in healthy subjects. mimNumber 168820 referenceNumber 44 publisherAbbreviation HighWire pubmedID 11238489 source J. Clin. Endocr. Metab. 86: 1078-1082, 2001. authors Paolisso, G., Manzella, D., Tagliamonte, M. R., Barbieri, M., Marfella, R., Zito, G., Bonafe, M., Giugliano, D., Franceschi, C., Varricchio, M. pubmedImages false publisherUrl http://highwire.stanford.edu title Paraoxonase 1 status in the Thai population. mimNumber 168820 referenceNumber 45 pubmedID 15924216 source J. Hum. Genet. 50: 293-300, 2005. authors Phuntuwate, W., Suthisisang, C., Koanantakul, B., Mackness, M. I., Mackness, B. pubmedImages false articleUrl http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=1003443 publisherName HighWire Press title Genetic polymorphism and interethnic variability of plasma paroxonase activity. mimNumber 168820 referenceNumber 46 publisherAbbreviation HighWire pubmedID 1003443 source J. Med. Genet. 13: 337-342, 1976. authors Playfer, J. R., Eze, L. C., Bullen, M. F., Evans, D. A. P. pubmedImages false publisherUrl http://highwire.stanford.edu source New York: Oxford Univ. Press (pub.) 1988. mimNumber 168820 authors Roychoudhury, A. K., Nei, M. title Human Polymorphic Genes: World Distribution. referenceNumber 47 title Linkage between the loci for cystic fibrosis and paraoxonase. mimNumber 168820 referenceNumber 48 pubmedID 3017612 source Clin. Genet. 29: 374-377, 1986. authors Schmiegelow, K., Eiberg, H., Tsui, L.-C., Buchwald, M., Phelan, P. D., Williamson, R., Warwick, W., Niebuhr, E., Mohr, J., Schwartz, M., Koch, C. pubmedImages false articleUrl http://dx.doi.org/10.1172/JCI118373 publisherName Journal of Clinical Investigation title A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. mimNumber 168820 referenceNumber 49 publisherAbbreviation JCI pubmedID 8675673 source J. Clin. Invest. 96: 3005-3008, 1995. authors Serrato, M., Marian, A. J. pubmedImages false publisherUrl http://www.jci.org articleUrl http://dx.doi.org/10.1038/28406 publisherName Nature Publishing Group title Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. mimNumber 168820 referenceNumber 50 publisherAbbreviation NPG pubmedID 9685159 source Nature 394: 284-287, 1998. authors Shih, D. M., Gu, L., Xia, Y.-R., Navab, M., Li, W.-F., Hama, S., Castellani, L. W., Furlong, C. E., Costa, L. G., Fogelman, A. M., Lusis, A. J. pubmedImages false publisherUrl http://www.nature.com title Serum arylesterase levels of activity in twins and their parents. mimNumber 168820 referenceNumber 51 pubmedID 5107117 source Am. J. Hum. Genet. 23: 375-382, 1971. authors Simpson, N. E. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(85)71261-X publisherName Elsevier Science title The genetic mapping and gene structure of mouse paraoxonase/arylesterase. mimNumber 168820 referenceNumber 52 publisherAbbreviation ES pubmedID 8825627 source Genomics 30: 431-438, 1995. authors Sorenson, R. C., Primo-Parmo, S. L., Camper, S., La Du, B. N. pubmedImages false publisherUrl http://www.elsevier.com/ title Genetic variation and evolution of the carboxylic esterases and carbonic anhydrases of primate erythrocytes. mimNumber 168820 referenceNumber 53 pubmedID 14295494 source Am. J. Hum. Genet. 17: 257-272, 1965. authors Tashian, R. E. pubmedImages false title Inheritance of an erythrocyte acetylesterase variant of man. mimNumber 168820 referenceNumber 54 pubmedID 13919743 source Am. J. Hum. Genet. 14: 295-300, 1962. authors Tashian, R. E., Shaw, M. W. pubmedImages false articleUrl http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=2997931 publisherName HighWire Press title Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. mimNumber 168820 referenceNumber 55 publisherAbbreviation HighWire pubmedID 2997931 source Science 230: 1054-1057, 1985. authors Tsui, L.-C., Buchwald, M., Barker, D., Braman, J. C., Knowlton, R., Schumm, J. W., Eiberg, H., Mohr, J., Kennedy, D., Plavsic, N., Zsiga, M., Markiewicz, D., Akots, G., Brown, V., Helms, C., Gravius, T., Parker, C., Rediker, K., Donis-Keller, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0960-314X&volume=11&issue=2&spage=123 publisherName Lippincott Williams & Wilkins title Rabbits possess a serum paraoxonase polymorphism similar to the human Q192R. mimNumber 168820 referenceNumber 56 publisherAbbreviation LWW pubmedID 11266077 source Pharmacogenetics 11: 123-134, 2001. authors Watson, C. E., Draganov, D. I., Billecke, S. S., Bisgaier, C. L., La Du, B. N. pubmedImages false publisherUrl http://www.lww.com/ articleUrl http://link.springer.de/link/service/journals/00439/bibs/7101001/71010067.htm publisherName Springer title The arg-192 isoform of paraoxonase with low sarin-hydrolyzing activity is dominant in the Japanese. mimNumber 168820 referenceNumber 57 publisherAbbreviation Springer pubmedID 9385372 source Hum. Genet. 101: 67-68, 1997. authors Yamasaki, Y., Sakamoto, K., Watada, H., Kajimoto, Y., Hori, M. pubmedImages false publisherUrl http://www.springeronline.com/ status live mimNumber 168820 dateCreated Mon, 02 Jun 1986 03:00:00 EDT clinicalSynopsis headAndNeckTeethExists false headAndNeckNeckExists false skinNailsHairSkinHistologyExists false oldFormatExists true skinNailsHairSkinExists false miscellaneousExists false headAndNeckEyesExists false abdomenBiliaryTractExists false skinNailsHairExists false headAndNeckMouthExists false genitourinaryBladderExists false skeletalSkullExists false chestDiaphragmExists false neurologicCentralNervousSystemExists false immunologyExists false genitourinaryExists false skeletalPelvisExists false neurologicBehavioralPsychiatricManifestationsExists false molecularBasisExists false growthExists false genitourinaryUretersExists false abdomenGastrointestinalExists false skeletalHandsExists false skeletalExists false skeletalFeetExists false creationDate Undefined genitourinaryExternalGenitaliaFemaleExists false genitourinaryInternalGenitaliaFemaleExists false growthOtherExists false growthWeightExists false laboratoryAbnormalitiesExists false voiceExists false metabolicFeaturesExists false growthHeightExists false endocrineFeaturesExists false skinNailsHairNailsExists false neurologicExists false prenatalManifestationsMovementExists false abdomenSpleenExists false respiratoryExists false hematologyExists false prenatalManifestationsDeliveryExists false skinNailsHairHairExists false prenatalManifestationsPlacentaAndUmbilicalCordExists false genitourinaryInternalGenitaliaMaleExists false genitourinaryExternalGenitaliaMaleExists false headAndNeckExists false neurologicPeripheralNervousSystemExists false cardiovascularHeartExists false editHistory Undefined respiratoryLungExists false abdomenExists false headAndNeckFaceExists false skeletalLimbsExists false cardiovascularExists false cardiovascularVascularExists false headAndNeckHeadExists false abdomenPancreasExists false headAndNeckEarsExists false genitourinaryKidneysExists false respiratoryNasopharynxExists false respiratoryAirwaysExists false skeletalSpineExists false chestRibsSternumClaviclesAndScapulaeExists false neoplasiaExists false abdomenLiverExists false chestBreastsExists false prenatalManifestationsMaternalExists false skinNailsHairSkinElectronMicroscopyExists false inheritanceExists false prenatalManifestationsExists false headAndNeckNoseExists false abdomenExternalFeaturesExists false chestExists false prenatalManifestationsAmnioticFluidExists false respiratoryLarynxExists false chestExternalFeaturesExists false muscleSoftTissueExists false oldFormat Misc Organophosphate poisoning sensitvity; Lab Low paroxonase (arylesterase hydrolyzing paroxon to produce p-nitrophenol); Inheritance Autosomal dominant (7q21-q22) {HPO HP:0000006 UMLS:C0443147}; epochCreated 518079600 phenotypicSeriesExists true creationDate Victor A. McKusick : 6/2/1986 epochUpdated 1347606000 textSectionList textSection textSectionTitle Description textSectionContent The paraoxonase (PON) gene family includes 3 genes, PON1, PON2 ({602447}), and PON3 ({602720}), aligned next to each other on chromosome 7. PON1 ({EC 3.1.1.2}) hydrolyzes the toxic oxon metabolites of several organophosphorous insecticides, including parathion, diazinon, and chlorpyrifos, as well as nerve agents, such as sarin and soman. PON1 also hydrolyzes aromatic esters, preferably those of acetic acid. In addition, PON1 hydrolyzes a variety of aromatic and aliphatic lactones, and it also catalyzes the reverse reaction, lactonization, of gamma- and delta-hydroxycarboxylic acids. Human PON1 is synthesized in liver and secreted into blood, where it is associated exclusively with high density lipoproteins (HDLs) and may protect against development of atherosclerosis ({15:Draganov et al., 2005}). textSectionName description textSectionTitle Cloning textSectionContent {25:Hassett et al. (1991)} isolated a full-length PON1 cDNA from a human liver cDNA library using rabbit Pon1 as a hybridization probe. The deduced PON1 protein contains 355 amino acids and is more than 85% similar to the rabbit protein. N-terminal sequences derived from purified rabbit and human PON1 proteins suggested that the PON1 signal sequence is retained, except for the initiator methionine. Characterization of the rabbit and human PON1 cDNAs confirmed that the signal sequences are not processed, except for the N-terminal methionine. Using SDS-PAGE, {15:Draganov et al. (2005)} found that PON1 appeared as a doublet of about 39 and 42 kD. However, using nondenaturing PAGE, they observed human serum PON1 and recombinant PON1 at apparent molecular masses of 91.9 and 95.6 kD, respectively, suggesting that PON1 forms dimers. Glycosidase treatment of human serum PON1 suggested that the secreted form of PON1 contains complex carbohydrates. {35:Lu et al. (2006)} stated that human PON1, PON2, and PON3 have 3 conserved cysteines. Cys41 and cys351 are predicted to form an intramolecular disulfide bond, and cys283 is predicted to be involved in antioxidant activity. textSectionName cloning textSectionTitle Gene Structure textSectionContent {11:Clendenning et al. (1996)} characterized a 28-kb contig encompassing 300 bp of 5-prime sequence, the entire coding region, and 2 kb of 3-prime flanking sequence of the PON1 gene. The structural portion of the paraoxonase protein is encoded by 9 exons that form the primary transcript through the use of typical splice donor and acceptor sites. {52:Sorenson et al. (1995)} showed that the Pon1 gene in mice contains 9 exons spanning approximately 25 to 26 kb. textSectionName geneStructure textSectionTitle Mapping textSectionContent {18:Eiberg and Mohr (1979)} presented linkage data. No linkage with any of 19 markers was found by {38:Mueller et al. (1983)}. {19:Eiberg et al. (1985)} showed that cystic fibrosis ({219700}) and PON are linked on chromosome 7 (maximum lod 3.70 at theta = 0.07 in males and 0.00 in females)--the first step in the cloning of the CF gene in 1989. {55:Tsui et al. (1985)} confirmed the PON-CF linkage by finding linkage of PON to a DNA marker that is also linked to CF. {48:Schmiegelow et al. (1986)} found the PON and CF loci linked with lod score of 3.46 at recombination fraction 0.07 in males and 0.13 in females. By in situ hybridization, {27:Humbert et al. (1993)} demonstrated that the PON gene maps to chromosome 7q21-q22. {37:Mochizuki et al. (1998)} pointed out that the PON1, PON2, and PON3 genes are physically linked on chromosome 7q21.3. {52:Sorenson et al. (1995)} mapped the mouse Pon1 gene to the proximal end of chromosome 6 by interspecific backcross analysis. {34:Li et al. (1997)} likewise mapped the gene to mouse chromosome 6. textSectionName mapping textSectionTitle Gene Function textSectionContent {51:Simpson (1971)} found a unimodal distribution of serum arylesterase activity in 176 individuals. There was no difference in enzyme activity between sexes, but the level of activity gradually increased with age. From a study of twins, heritability of arylesterase activity was estimated to be 74%. Data from parent pairs suggested that, in addition to genetic and age factors, unknown nongenetic factors substantially affected enzyme activity. {17:Eckerson et al. (1983)} concluded that arylesterase activity, measured with phenylacetate as substrate, and paraoxonase activity are determined by the same gene. They used the designation esterase A for the paraoxonase/arylesterase enzyme (see HISTORY for information on the identification and classification of esterases). {20:Furlong et al. (1991)} also demonstrated that both arylesterase and paraoxonase activities are expressed by a single enzyme. {21:Furlong et al. (1988)} studied hydrolysis of an insecticide metabolite, chlorpyrifos oxon, by PON1. The physiologic role of paraoxonase in detoxication and in intermediary metabolism is uncertain ({32:La Du, 1988}). However, animal studies, including examination of quantitative adequacy of PON and protection against paraoxon toxicity, correlation of LD50 values with PON levels, and demonstration that intravenously injected PON provides protection against paraoxon toxicity, indicate that serum PON is protective against organophosphate poisoning (reviewed by {27:Humbert et al., 1993}). In a series of animal experiments, {39:Navab et al. (1997)} demonstrated that the ratio of Apoj ({185430}) to Pon was increased in fatty streak-susceptible mice fed an atherogenic diet, in Apoe knockout mice on a chow diet, in LDL receptor (LDLR; {606945}) knockout mice on a cholesterol-enriched diet, and in fatty streak-susceptible mice injected with mildly oxidized LDL fed a chow diet. Human studies showed that the APOJ/PON ratio was significantly higher than that of controls in 14 normolipidemic patients with coronary artery disease in whom the cholesterol/HDL ratio did not differ significantly from that of controls. {15:Draganov et al. (2005)} found that glycosylation of recombinant PON1 with high-mannose-type sugars did not alter its enzymatic activity, but it may have affected protein stability. They found that PON1, PON2, and PON3, whether expressed in insect or HEK293 cells, metabolized oxidized forms of arachidonic acid and docosahexaenoic acid. Otherwise, the PONs showed distinctive substrate specificities. PON1, but not other PONs, specifically hydrolyzed organophosphates. About 60% of total arylesterase and lactonase activity of PON1-transfected HEK293 cells was secreted into the culture medium. {15:Draganov et al. (2005)} found that recombinant PONs did not protect human LDL against Cu(2+)-induced oxidation in vitro, and no antioxidant activity copurified with any of the PONs. They stated that they had previously copurified antioxidant activity with human serum PON1, but that it was attributable to a low molecular mass contaminant and to the detergent in the preparation. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent Variation in PON1 Enzyme Activity {24:Geldmacher-von Mallinckrodt et al. (1973)} first found polymorphism of paraoxonase activity. {46:Playfer et al. (1976)} found bimodality for plasma paraoxonase activity in British and Indian persons, defining low and high activity phenotypes. Study of 40 British families confirmed this genetic polymorphism. Two phenotypes controlled by 2 alleles at 1 autosomal locus were defined. The frequency of the low activity phenotype was lower in the Indian population than in the British population. Malay, Chinese, and African populations failed to show clear bimodality. Possibly multiple alleles are present in these populations and result in a continuous distribution. {38:Mueller et al. (1983)} described a test based on the differential inhibition of EDTA of plasma paraoxonase from persons with the high activity allele. With this test, trimodality of activity levels was suggested by population studies. The gene frequency of the low activity allele in 531 Seattle blood donors of European origin was 0.72. Family studies were consistent with codominant autosomal inheritance of 2 alleles encoding products with low and high activity levels. {17:Eckerson et al. (1983)} could clearly distinguish heterozygotes from both homozygous phenotypes on the basis of the ratio of paraoxonase to arylesterase activities. {43:Ortigoza-Ferado et al. (1984)} concluded that albumin has paraoxonase activity and proposed that an optimal assay of polymorphic paraoxonase activity should be based on activity of the nonalbumin fraction. {41:Nielsen et al. (1986)} reexamined extensive family data and reaffirmed that segregation into high and low paraoxonase activity is largely or exclusively due to a 1-locus system. {27:Humbert et al. (1993)} found that arginine at position 192 of PON1 specifies high-activity plasma paraoxonase, whereas glutamine at this position specifies a low-activity variant (Q192R; {168820.0001}). This polymorphism is also referred to as gln191 to arg. {1:Adkins et al. (1993)} demonstrated that glutamine or arginine at amino acid 191 determines the A and B allozymes, respectively, of PON1. In a study of 376 white individuals, {7:Brophy et al. (2001)} determined the genotypes of 3 regulatory region polymorphisms and examined their effect on plasma PON1 levels as indicated by rates of phenylacetate hydrolysis. The -108C-T polymorphism ({168820.0003}) had a significant effect on PON1 activity level, whereas a polymorphism at position -162 had a lesser effect. A polymorphism at position -909, which is in linkage disequilibrium with the other sites, appeared to have little or no independent effect on PON1 activity level in vivo. {7:Brophy et al. (2001)} presented evidence that the effect of the L55M ({168820.0002}) polymorphism on lowered paraoxonase activity is not due primarily to the amino acid change itself but to linkage disequilibrium with the -108C-T regulatory region polymorphism. The L55M polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108C-T and Q192R polymorphisms were made. The -108C-T polymorphism accounted for 22.8% of the observed variability in PON1 expression levels, which was much greater than that attributable to other PON1 polymorphisms. Using a validated microsomal expression system of metabolizing enzymes, {6:Bouman et al. (2011)} identified PON1 as the crucial enzyme for the bioactivation of the antiplatelet drug clopidogrel, with the common Q192R polymorphism determining the rate of active metabolite formation. Analysis of patients with coronary artery disease who underwent stent implantation and received clopidogrel therapy revealed that Q192 homozygotes were more likely to undergo stent thrombosis than patients with the RR192 or QR192 genotypes (odds ratio, 3.6; p = 0.0003). Susceptibility to Organophosphate Poisoning PON1 hydrolyzes diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. {9:Cherry et al. (2002)} studied PON1 polymorphisms in 175 farmers with ill health that they attributed to sheep dip and 234 other farmers nominated by the ill farmers and thought to be in good health despite having also dipped sheep. They calculated odds ratios for the Q192R ({168820.0001}) and L55M ({168820.0002}) polymorphisms, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least 1 R allele at position 192 (odds ratio 1.93), both alleles of type LL (odds ratio 1.70) at position 55, and to have diazoxonase activity below normal median (odds ratio 1.77). The results supported the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep. Susceptibility to Coronary Artery Disease {49:Serrato and Marian (1995)}, who referred to the gln192-to-arg (Q192R; {168820.0001}) polymorphism as the A/G polymorphism or the A/B polymorphism, demonstrated a relationship to coronary artery disease. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. Individuals with the A genotype have a lower enzymatic activity than those with the B genotype. {49:Serrato and Marian (1995)} determined the genotypes in 223 patients with angiographically documented coronary artery disease and in 247 individuals in the general population. The distribution of genotypes was in Hardy-Weinberg equilibrium in both groups. Genotypes A and B were present in 49% and 11% of control individuals and in 30% and 18% of patients with coronary artery disease, respectively (p = 0.0003). The frequency of the A allele was 0.69 in controls and 0.56 in patients (p = 0.0001). There was no difference in the distribution of PON genotypes in the subgroups of patients with restenosis, myocardial infarction, or any of the conventional risk factors for coronary artery disease as compared with corresponding subgroups. The L55M and Q192R polymorphisms in the PON1 gene and the ser311-to-cys (S311C; {602447.0001}) polymorphism in the PON2 gene are associated with the risk of coronary artery disease in several European or European-derived populations. {8:Chen et al. (2003)} examined the association between these 3 markers and the severity of coronary artery disease as determined by the number of diseased coronary artery vessels in 711 women. No significant association was found between the PON polymorphisms and stenosis severity in either white or black women. However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON codon 192 arg/arg genotype was significantly higher in the group with 3-vessel disease than in the other groups (those with 1-vessel and 2-vessel disease) combined. Similarly, the frequency of the PON2 codon 311 cys/cys genotype was significantly higher in the group with 3-vessel disease than in the other groups combined. The adjusted odds ratio for the development of 3-vessel disease was 2.80 for PON1 codon 192 arg/arg and 3.68 for PON2 codon 311 cys/cys. The data indicated that the severity of coronary artery disease, in terms of the number of diseased vessels, may be affected by common genetic variation in the PON gene cluster on chromosome 7. {22:Garin et al. (1997)} identified homozygosity for the leu54 allele of PON1 ({168820.0002}), which is associated with high paraoxonase activity, as an independent risk factor for cardiovascular disease. A linkage disequilibrium was apparent between the polymorphisms giving rise to leu54 and arg191. {22:Garin et al. (1997)} stated that their study underlined the fact that susceptibility to cardiovascular disease correlated with high-activity paraoxonase alleles. Linkage disequilibrium could explain the association between both the leu54 and the arg191 polymorphisms and cardiovascular disease. Susceptibility to Coronary Artery Spasm {29:Ito et al. (2002)} found that the incidence of the PON1 192R allele was significantly higher in a cohort of 214 Japanese patients with coronary spasm than in 212 control subjects. They speculated that the high frequency of the PON1 arg192 allele may be related to the higher prevalence of coronary spasm among Japanese than among Caucasians. Susceptibility to Microvascular Complications of Diabetes 5 {31:Kao et al. (1998)} found an association between the L55M polymorphism in the PON1 gene ({168820.0002}) and diabetic retinopathy (MVCD5; {603933}) in patients with type 1 diabetes ({222100}). {30:Kao et al. (2002)} confirmed the association between L55M and diabetic retinopathy, finding increased susceptibility for retinopathy with the leu/leu genotype (odds ratio 3.34; p less than 0.0001). Other Associations {28:Ikeda et al. (2001)} found that the distribution of the Q192R and L55M ({168820.0002}) polymorphisms in the PON1 gene was significantly different between Japanese patients with exudative age-related macular degeneration (ARMD; see {153800}) and age- and sex-matched controls. The BB genotype at position 192 and the LL genotype at position 55 occurred at higher frequency in patients with ARMD compared to controls (p = 0.0127 and p = 0.0090, respectively). The mean oxidized LDL level in patients was significantly higher than in controls (p less than 0.01). {28:Ikeda et al. (2001)} concluded that the PON1 gene polymorphisms might represent a genetic risk factor for ARMD and that increased plasma oxidized LDL might be involved in the pathogenesis of ARMD. Data on gene frequencies of allelic variants were tabulated by {47:Roychoudhury and Nei (1988)}. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent {13:Davies et al. (1996)} analyzed the paraoxonase catalytic activity against the toxic oxon forms which result from the bioactivation of the organophosphorus insecticides parathion, chloropyrifos, and diazinon in the P450 system. They also analyzed the hydrolytic activity of PON1 against the nerve agents soman and sarin. {13:Davies et al. (1996)} reported a simple enzyme analysis that provided a clear resolution of PON1 genotypes and phenotypes. The plot of diazoxon hydrolysis versus paraoxon hydrolysis clearly resolved all 3 genotypes (Q192Q192, Q191R192, R192R192; see {168820.0001}) and at the same time provided important information about the level of enzyme activity in an individual. They observed the reversal of the effect of PON1 polymorphisms for diazoxon hydrolysis relative to paraoxon hydrolysis. RR homozygotes (high paraoxonase activity) had lower diazoxonase activity than the QQ homozygotes (low paraoxonase activity). They reported that the effect was also reversed for the nerve gases soman and sarin (sarin was the nerve gas released in the Tokyo subway in March 1995). The mean value of sarin hydrolysis was only 38 U per liter for the R192 homozygotes compared with 355 U per liter for the Q192 homozygotes. {13:Davies et al. (1996)} observed an increased frequency for the R192 allele (0.41) in the Hispanic population compared with a frequency of 0.31 for populations of northern European origin. These frequencies result in approximately 16% of individuals of Hispanic origin being homozygous for the R192 PON1 isoform compared with 9% of individuals of northern European origin. They noted that newborns have very low activities of PON1, leading them to predict that newborns would be significantly more sensitive to organophosphorus compounds than adults. The authors cited studies showing that injected PON1 protects against organophosphorus poisoning in rodents ({33:Li et al., 1995}). {45:Phuntuwate et al. (2005)} studied the activity of 4 PON1 polymorphisms towards paraoxon, phenylacetate, and diazoxon. They found that the L55M, Q192R, and -909G-C polymorphisms significantly and variably affected serum PON1 activity towards the substrates, whereas the -108C-T polymorphism had no significant effect on serum PON1 activity towards any substrate. {45:Phuntuwate et al. (2005)} suggested that the physiologic relevance of the PON1 polymorphisms is that they are associated with significant differences in serum PON1 activity that are substrate dependent. {36:Mackness et al. (1998)} examined the effects of the 2 common polymorphisms in PON1 on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective in protecting LDL, while HDL from RR/LL homozygotes was least effective. Thus after 6 hours of coincubation of HDL and LDL with Cu(2+), PON1-QQ HDL retained 57 +/- 6.3% of its original ability to protect LDL from oxidative modification, while PON1-QR HDL retained less at 25.1 +/- 4.5% and PON1-RR HDL retained only 0.75 +/- 0.40%. In similar experiments, HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6%, respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3%. PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation. textSectionName genotypePhenotypeCorrelations textSectionTitle Animal Model textSectionContent To study the role of PON1 in vivo, {50:Shih et al. (1998)} created Pon1-knockout mice by gene targeting. Compared with their wildtype littermates, Pon1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from Pon1-deficient mice were unable to prevent LDL oxidation in a cocultured cell model of the artery wall, and both HDLs and LDLs isolated from Pon1-knockout mice were more susceptible to oxidation by cocultured cells than were lipoproteins from wildtype littermates. When fed on a high-fat, high-cholesterol diet, Pon1-null mice were more susceptible to atherosclerosis than were their wildtype littermates. {56:Watson et al. (2001)} identified a serum paraoxonase polymorphism in rabbit with functional characteristics similar to those of human Q192R. They suggested that the rabbit may serve as a model in examining the effect of human PON1 polymorphisms in disease development. textSectionName animalModel textSectionTitle History textSectionContent Identification and Classification of Esterases Using azo dye coupling techniques and electrophoresis, {53:Tashian (1965)} defined several different esterases in human red cells. Three main groups, differing as to electrophoretic properties, substrate specificities and inhibition characteristics, were A, B, and C esterases. Variants of esterase A were reported by {54:Tashian and Shaw (1962)} and {53:Tashian (1965)}. Using starch-gel electrophoresis, {12:Coates et al. (1975)} identified multiple esterase isozymes in every human tissue, and they characterized the isozymes in terms of electrophoretic mobility, tissue distribution, developmental changes in utero, substrate specificity, inhibition properties, and molecular weight. On these criteria, 13 sets of esterase isozymes were identified, in addition to the esterase isozymes due to cholinesterase and carbonic anhydrase. The data suggested that the 13 sets of isozymes are determined by at least 9 different genes. The acetylesterases, which prefer acetate esters as substrates, were divided into 9 sets of isozymes, designated ESA1 to ESA7, ESC ({133270}), and ESD ({133280}). {12:Coates et al. (1975)} divided the butyrylesterases, which prefer butyrate esters as substrates, into 4 sets of isozymes, designated ESB1 to ESB4. textSectionName history seeAlso Augustinsson and Henricson (1966); Eckerson et al. (1983); Geldmacher-von Mallinckrodt (1978); Neel et al. (1977) externalLinks mgiIDs MGI:103295 cmgGene false mgiHumanDisease true ncbiReferenceSequences 209413720 refSeqAccessionIDs NG_008779.1 dermAtlas false hprdIDs 01351 swissProtIDs P27169 zfinIDs ZDB-GENE-040912-6 uniGenes Hs.370995 gtr true wormbaseIDs WBGene00138653,WBGene00118847,WBGene00140888,WBGene00056635,WBGene00033068,WBGene00118848,WBGene00033067,WBGene00118849,WBGene00090844,WBGene00077701,WBGene00003170,WBGene00010775,WBGene00031865,WBGene00044697,WBGene00062344,WBGene00017089,WBGene00062343,WBGene00153067,WBGene00096103 umlsIDs C1418754,C2674663,C2674662,C3149706,C1840169 genbankNucleotideSequences 148146385,164696404,408207,4105840,15637344,1304129,22532482,1575041,1262346,9873996,143806601,27948087,51094869,1575033,298531,1333629,511811563,511811562,408298,190191,50959527,3598727,190195,15637340,190193,74230038,1280040 geneTests false approvedGeneSymbols PON1 geneIDs 5444 proteinSequences 298532,50959528,51094888,2795823,408299,189054217,4105841,15637345,190194,1304130,190192,19923106,15637341,22532483,190196,1262347,119597177,308153572,1280041,1575043,7705003 nextGxDx false

entryList

entry status live allelicVariantExists true epochCreated 806742000 geneMap geneSymbols CPT2, IIAE4 sequenceID 485 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 600650 phenotypeInheritance Autosomal recessive phenotype CPT deficiency, hepatic, type II phenotypeMimNumber 600649 phenotypeMappingKey 3 mimNumber 600650 phenotypeInheritance Autosomal recessive phenotype CPT II deficiency, lethal neonatal phenotypeMimNumber 608836 phenotypeMappingKey 3 mimNumber 600650 phenotypeInheritance Autosomal recessive phenotype Myopathy due to CPT II deficiency phenotypeMimNumber 255110 phenotypeMimNumber 614212 mimNumber 600650 phenotypeInheritance Autosomal recessive; Autosomal dominant phenotypicSeriesMimNumber 601551 phenotypeMappingKey 3 phenotype {Encephalopathy, acute, infection-induced, 4, susceptibility to} chromosomeLocationStart 53662100 chromosomeSort 485 chromosomeSymbol 1 mimNumber 600650 geneInheritance None confidence C mappingMethod REa, A geneName Carnitine palmitoyltransferase II comments formerly at 1p13 mouseMgiID MGI:109176 mouseGeneSymbol Cpt2 computedCytoLocation 1p32.3 cytoLocation 1p32 transcript uc001cvb.4 chromosomeLocationEnd 53679868 chromosome 1 contributors Cassandra L. Kniffin - updated : 9/19/2011 Cassandra L. Kniffin - updated : 4/9/2009 Cassandra L. Kniffin - updated : 12/3/2007 Cassandra L. Kniffin - updated : 5/10/2005 Cassandra L. Kniffin - reorganized : 8/23/2004 Cassandra L. Kniffin - updated : 8/19/2004 Natalie E. Krasikov - updated : 8/10/2004 Victor A. McKusick - updated : 6/11/2003 Victor A. McKusick - updated : 2/11/2003 John A. Phillips, III - updated : 10/8/2002 Sonja A. Rasmussen - updated : 8/24/2001 Victor A. McKusick - updated : 2/15/2001 Victor A. McKusick - updated : 9/24/1999 Victor A. McKusick - updated : 10/26/1998 Victor A. McKusick - updated : 3/27/1998 clinicalSynopsisExists false mimNumber 600650 allelicVariantList allelicVariant status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE dbSnps rs74315293 text In a patient with infantile carnitine palmitoyltransferase II deficiency ({600649}), {26:Taroni et al. (1992)} identified homozygosity for a mutant CPT2 allele (termed the 'ICV' allele) that carried 3 missense changes: a 1203G-A transition predicting a val368-to-ile substitution (V368I); a 1992C-T transition predicting an arg631-to-cys substitution (R631C); and a 2040A-G transition predicting a met647-to-val substitution (M647V). Screening of 59 healthy controls demonstrated that both the V368I and M647V mutations are sequence polymorphisms with allele frequencies of 0.5 and 0.25, respectively. The R631C substitution was not detected in 22 normal individuals or in 12 of 14 CPTase II-deficient patients with the adult muscular form of CPT II deficiency ({255110}). Notably, 2 of the adult CPTase II-deficient patients were heterozygous for the triply mutant ICV allele, suggesting compound heterozygosity for this and a different mutant allele. In vitro functional expression studies showed that the R631C substitution drastically depressed catalytic activity of the CPT II protein. The V368I and M647V mutations, although not affecting enzyme activity alone, exacerbated the effects of the R631C substitution. In a Dutch patient with adult-onset CPT II deficiency, {25:Taroni et al. (1993)} identified compound heterozygosity for the R631C mutation and the S113L mutation ({600650.0002}). Another unrelated Italian patient with the adult-onset form had the R631C mutation on 1 allele. mutations CPT2, ARG631CYS number 1 alternativeNames CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET, INCLUDED clinvarAccessions RCV000009509;;1;;;RCV000009508;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs74315294 text In 8 unrelated patients with familial recurrent myoglobinuria due to carnitine palmitoyltransferase II deficiency ({255110}), {25:Taroni et al. (1993)} identified a homozygous 439C-T transition in the CPT2 gene, resulting in a ser133-to-leu substitution (S133L). One of the patients had been reported by {8:DiDonato et al. (1978)}. Among a total of 25 patients with the disorder, {25:Taroni et al. (1993)} found the S113L mutation in 56% of the mutant CPT II alleles and concluded that the S113L missense mutation is the most frequent change found in CPT II deficiency. One Dutch patient was compound heterozygous for the S113L mutation and the R631C ({600650.0001}) mutation. In vitro functional expression studies showed that the S113L mutation resulted in normal protein synthesis, but a markedly reduced steady-state level, indicating decreased stability of the mutant protein. By in vitro functional analysis in fibroblasts, {4:Bonnefont et al. (1996)} showed that the S113L mutation resulted in 20% CPT II residual activity with no consequence on long-chain fatty acid (LCFA) oxidation, whereas the Y628S mutation ({600650.0005}), found in the more severe infantile form of the disorder ({600649}), resulted in 10% CPT II residual activity and markedly impaired LCFA oxidation. {4:Bonnefont et al. (1996)} concluded that CPT II activity must be reduced below a critical threshold for LCFA oxidation in fibroblasts to be impaired. This critical threshold differs among tissues, thus providing a basis for the phenotypic heterogeneity of CPT II deficiency. In 3 related patients with CPT II deficiency from consanguineous marriages, 2 sibs and a first cousin, {13:Handig et al. (1996)} identified homozygosity for the S113L mutation. The cases could be traced back to a common ancestral couple 5 generations earlier. The family showed clinical variability of the disorder. {16:Martin et al. (1999)} identified the S113L mutation in 8 of 14 Spanish patients from 10 unrelated families. Seven patients were homozygous for the mutation, 1 patient was heterozygous, and 6 patients did not carry the mutation on either allele. The mutation was found in the heterozygous state in 7 healthy relatives belonging to 3 different families. mutations CPT2, SER113LEU number 2 clinvarAccessions RCV000009510;;1;;;RCV000078121;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs28936375 text In patients with the late-onset form of CPT II deficiency ({255110}), {28:Verderio et al. (1995)} identified a 665C-A transversion in exon 1 of the CPT2 gene, resulting in a pro50-to-his (P50H) substitution. This amino acid substitution occurred within a leucine-proline motif that is highly conserved in acyltransferases from different species. The mutation was detected in both alleles of a patient of Italian ancestry and in 1 allele of 1 patient each of Italian, Dutch, and French ancestry. {30:Vladutiu et al. (2002)} reported a male infant of mixed heritage with the late infantile form of CPT II ({600649}) who was compound heterozygous for the P50H mutation and for a truncating 2-bp deletion (see {600650.0009}). He presented at age 11 months with hypoglycemia, vomiting, and lethargy after a febrile illness. Dietary management was successful, and he was normal appearing at age 5 years. CPT II activity in fibroblasts was 17% of normal. {30:Vladutiu et al. (2002)} noted that the P50H mutation is usually associated with late-onset disease and postulated that compound heterozygosity for a mild and a severe CPT2 mutation causes an intermediate phenotype. mutations CPT2, PRO50HIS number 3 alternativeNames CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE, INCLUDED clinvarAccessions RCV000009511;;1;;;RCV000009512;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs28936376 text In a patient of Italian ancestry with late-onset CPT II deficiency ({255110}), {28:Verderio et al. (1995)} identified compound heterozygosity for 2 mutations in the CPT2 gene: a 2173G-A transition in exon 5, resulting in an asp553-to-asn (D553N) substitution, and S113L ({600650.0002}). Immunoblot analysis demonstrated that both mutations were associated with a markedly reduced steady-state level of the protein, indicating decreased stability of the mutant gene product. mutations CPT2, ASP553ASN number 4 clinvarAccessions RCV000009513;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE dbSnps rs28936673 text In an infant with the infantile form of CPT II deficiency ({600649}) originally reported by {7:Demaugre et al. (1991)}, {4:Bonnefont et al. (1996)} identified a homozygous 2399A-C transversion in the CPT2 gene, resulting in a tyr628-to-ser (Y628S) substitution. In vitro functional analysis in fibroblasts showed that the Y628S mutation resulted in 10% CPT II residual activity and markedly impaired oxidation of long-chain fatty acids, whereas the S113L ({600650.0002}) mutation found in the less severe adult form of the disorder ({255110}) resulted in 20% CPT II residual activity, without consequence on LCFA oxidation. {4:Bonnefont et al. (1996)} concluded that CPT II activity must be reduced below a critical threshold for LCFA oxidation in fibroblasts to be impaired. This critical threshold differs among tissues, thus providing a basis for the phenotypic heterogeneity of CPT II deficiency. {16:Martin et al. (1999)} reported a patient with late-onset CPT II deficiency who had the Y628S mutation on 1 allele. mutations CPT2, TYR628SER number 5 alternativeNames CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET, INCLUDED clinvarAccessions RCV000009514;;1;;;RCV000009515;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE dbSnps rs28936674 text In 2 Japanese sibs with the infantile form of CPT II deficiency ({600649}), {33:Yamamoto et al. (1996)} identified compound heterozygosity for 2 mutations in the CPT2 gene: a 621G-A transition resulting in a glu174-to-lys (E174K) substitution, and a 1249T-A transversion resulting in a phe383-to-tyr (F383Y; {600650.0007}) substitution. mutations CPT2, GLU174LYS number 6 clinvarAccessions RCV000009516;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE dbSnps rs74315295 text See {600650.0006} and {33:Yamamoto et al. (1996)}. {2:Aoki et al. (2007)} reported a 21-year-old Japanese woman with late-onset CPT II deficiency ({255110}) associated with a homozygous F383Y mutation. At age 19 and again at age 21, she had episodes of myalgia, dark urine, and increased serum creatine kinase during viral illnesses. Residual CPT2 activity ranged from 2 to 7% of normal controls, which the authors noted was usually associated with the more severe form of the disorder. Family history revealed a brother and sister who both died as infants. mutations CPT2, PHE383TYR number 7 alternativeNames CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET, INCLUDED clinvarAccessions RCV000009518;;1;;;RCV000009517;;1 status live name MYOPATHY, VARIABLE dbSnps rs74315296 text {31,29:Vladutiu et al. (1998, 2000)} reported a family in which a woman, her father, and her son were heterozygous for an arg503-to-cys (R503C) mutation in a highly conserved region of the CPT2 gene. Sequence analysis showed no other change in CPT2. The 54-year-old mother had a 35-year history of progressive muscle weakness and myopathic symptoms associated with reduced CPT II activity in lymphoblasts (47% of normal), fibroblasts (43%), and skeletal muscle (13%). Her 26-year-old son had a lifelong history of myopathic symptoms, whereas his grandfather had only mild weakness during childhood. The son had survived an episode of malignant hyperthermia during surgery at 4 years of age, during which CPK went to values greater than 5,000 mU/mL. Analysis of the V368I and M647V polymorphisms (see {600650.0001}) in the CPT2 gene showed that the mutant allele was linked to 368I and 647M in this family, and that the normal allele was linked to 647V in the affected patient and her son and to 647M in the patient's father. In common with malignant hyperthermia-associated mutations affecting skeletal muscle in the RYR1 ({180901}) and CACNL1A3 ({114208}) genes, the clinical, biochemical, and genetic evidence in this family suggested that the R503C substitution in CPT2 may cause a latent myopathy that becomes apparent only after specific anesthetic exposure. mutations CPT2, ARG503CYS number 8 clinvarAccessions RCV000009519;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs74315297 text {23:Taggart et al. (1999)} reported 4 Ashkenazi Jewish patients with late-onset CPT II deficiency ({255110}) who were compound heterozygous for a CPT2 allele with a 2-bp deletion, which they termed 413delAG, and a phe448-to-leu (F448L) substitution, and for the S113L ({600650.0002}) mutation. The 2-bp deletion causes a premature termination codon at residue 420; thus, the F448L change is not contained within the truncated protein and does not have functional significance. {9:Elpeleg et al. (2001)} reported 2 Ashkenazi Jewish sibs with the antenatal form of CPT II deficiency ({608836}) who were homozygous for the allele carrying the 2 mutations in exon 4 of the CPT2 gene; the 1-bp deletion, which they termed 1237delAG, and the F448L mutation. Both sibs had periventricular calcifications and markedly enlarged kidneys found in the fifth gestational month. Activity of CPT II in lymphocytes was undetectable. The 1237delAG mutation was predicted to result in a truncated protein at 65% of its normal length. Referring to the findings of {23:Taggart et al. (1999)}, {9:Elpeleg et al. (2001)} suggested that this allele is common in the Ashkenazi Jewish population. {30:Vladutiu et al. (2002)} reported a male infant of mixed heritage with the late infantile form of CPT II ({600649}) and episodic hypoglycemia who was compound heterozygous for the 2-bp deletion and the P50H ({600650.0003}) mutation. A male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II was compound heterozygous for the 2-bp deletion and a 3-bp deletion/5-bp insertion ({600650.0014}). mutations CPT2, 2-BP DEL, 1237AG AND PHE448LEU number 9 alternativeNames CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL, INCLUDED;; CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE, INCLUDED clinvarAccessions RCV000009520;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL text In a Moroccan family in which 4 sibs died from neonatal CPT II deficiency ({608836}), {22:Smeets et al. (2003)} identified a novel splice site mutation in the CPT2 gene: a G-to-A transition in the splice acceptor site of intron 2 ({600650.0011}). Studies at the mRNA level indicated that the affected children were homozygous for an insertion of a threonine at codon 534 (534insT) followed by a 25-bp deletion (bases 534-558). Studies of genomic DNA, however, revealed all patients were compound heterozygous for this 534insT/del25 mutation, and, on the other allele, for the novel splice site mutation. The findings underscored the incompleteness of mutation detection at the mRNA level in cases where a mutation leads to aberrant splicing or nonsense-mediated messenger decay. mutations CPT2, 1-BP INS, 534T/25-BP DEL, NT534 number 10 clinvarAccessions RCV000009523;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL text See {600650.0010} and {22:Smeets et al. (2003)}. mutations CPT2, IVS2AS, G-A, -1 number 11 clinvarAccessions RCV000009524;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL text In 2 sibs with lethal neonatal CPT II deficiency ({608836}) originally reported by {32:Witt et al. (1991)}, {12:Gellera et al. (1992)} identified a heterozygous 11-bp insertion mutation in exon 4 of the CPT2 gene (nucleotides 997-1007). The insertion results in a premature termination signal predicted to truncated the CPT2 protein by approximately 350 amino acids at the C terminus. The unaffected mother carried the insertion mutation, but the father had only wildtype alleles; {12:Gellera et al. (1992)} concluded that an additional, unidentified CPT2 mutation was present in the affected sibs. Cultured fibroblasts from the patients showed a 92% reduction in CPT II activity and virtual absence of the protein, indicating that complete CPT2 deficiency is a lethal condition. mutations CPT2, 11-BP DUP number 12 clinvarAccessions RCV000009525;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL dbSnps rs74315298 text In a premature Haitian infant with neonatal lethal CPT II deficiency ({608836}), {24:Taroni et al. (1994)} identified a homozygous mutation in exon 4 of the CPT2 gene, resulting in a pro227-to-leu (P227L) substitution. No CPT2 protein was detected by Western blot analysis of fibroblasts, and in vitro analysis demonstrated normal amounts of newly synthesized CPT II, suggesting decreased enzyme stability. CPT II residual activity was measured at less than 15% of normal control values. The parents were heterozygous for the mutation. {14:Isackson et al. (2008)} identified a homozygous P227L mutation in an African American patient with lethal neonatal CPT II deficiency. The infant appeared normal at birth but developed hypoglycemia in the nursery. She also had heart block, polycystic kidneys, and seizures, and died at age 14 days. Laboratory studies showed significantly increased plasma carnitine species. {14:Isackson et al. (2008)} noted that the P227L substitution is located at the C-terminal end of the beta-2 strand. The authors postulated that the mutation affects enzyme stability, since the affected residue is not near the active site. mutations CPT2, PRO227LEU number 13 clinvarAccessions RCV000009526;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL text In a male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II ({608836}) first reported by {1:Albers et al. (2001)}, {30:Vladutiu et al. (2002)} identified compound heterozygosity for a 2-bp deletion (see {600650.0009}) and a 109AGC-GCAGC change (3-bp deletion and 5-bp insertion) in the CPT2 gene. The infant died on the third day of life; CPT II activity was 6% and 18% of normal in fibroblasts and skeletal muscle, respectively. mutations CPT2, 3-BP DEL, 109AGC AND 5-BP INS, 109GCAGC number 14 clinvarAccessions RCV000009527;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs74315299 text {19:Orngreen et al. (2005)} identified a heterozygous glu454-to-ter (E454X) mutation in the CPT2 gene in a man who had experienced an episode of rhabdomyolysis after ingestion of alcohol and no food the night before a swimming practice. Residual CPT2 enzyme activity was 46% of normal control values, and biochemical studies indicated impaired fatty acid oxidation with prolonged exercise, which is consistent with myopathic late-onset CPT II deficiency ({255110}). {19:Orngreen et al. (2005)} suggested that the E454X truncated CPT2 protein may be incorporated into the tetrameric structure of the enzyme complex, resulting in a dominant-negative effect, and that some heterozygous carriers of CPT2 mutations may be symptomatic. mutations CPT2, GLU454TER number 15 clinvarAccessions RCV000009528;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET dbSnps rs74315300 text {19:Orngreen et al. (2005)} identified a heterozygous asp213-to-gly (D213G) mutation in the CPT2 gene in a woman with exercise intolerance and muscle cramps. Residual CPT2 enzyme activity was 65% of normal control values, and biochemical studies indicated impaired fatty acid oxidation with prolonged exercise, which is consistent with myopathic late-onset CPT II deficiency ({255110}). The D213G substitution occurs in a highly conserved domain of the protein, and the authors suggested that the change may compromise normal enzyme function. The woman had 2 children with late-onset CPT II deficiency caused by compound heterozygous mutations in the CPT2 gene: D213G and S113L ({600650.0002}). The asymptomatic father was heterozygous for the S113L mutation. {19:Orngreen et al. (2005)} suggested that some heterozygous carriers of CPT2 mutations may be symptomatic. mutations CPT2, ASP213GLY number 16 clinvarAccessions RCV000009529;;1 status live name CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE dbSnps rs121918528 text In a patient with infantile CPT II deficiency ({600649}), {14:Isackson et al. (2008)} identified a homozygous 359A-G transition in the CPT2 gene, resulting in a tyr120-to-cys (Y120C) substitution. The location of the mutation was predicted to interfere with the active site. CPT2 activity was 2.5% of control values. The patient presented at age 15 months following a febrile episode with hypoglycemic encephalopathy and hepatomegaly. There was complete neurologic recovery, and the patient did well with proper treatment. mutations CPT2, TYR120CYS number 17 clinvarAccessions RCV000009530;;1 status live name ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED, SUSCEPTIBILITY TO, 4 dbSnps rs2229291,rs1799821 text {6:Chen et al. (2005)} found an association between 2 thermolabile polymorphisms in the CPT1 gene and susceptibility to infection-induced acute encephalopathy-4 (IIAE4; {614212}) in Japanese children. The variants were a 1055T-G transversion, resulting in a phe352-to-cys (F352C) substitution ({dbSNP rs2229291}), and a 1102G-A transition, resulting in a val368-to-ile (V368I) substitution ({dbSNP rs1799821}). Four (30.8%) of 13 patients with the disorder carried these alleles, compared to 6 (7.6%) of 79 controls (p less than 0.025). In vitro functional studies in COS-7 cells showed that the 352C/368I allele had significantly reduced activity (34.7% compared to wildtype) at 37 degrees C, and was decreased even more at 41 degrees C (less than 30% of wildtype at 37 degrees). The 352C/368V allele showed less severely decreased activity (62.8% of wildtype) at 37 degrees C, with again a further decrease at 41 degrees C. {6:Chen et al. (2005)} noted that the allelic frequency of F352C in Japan is 0.21, and that this variant has not been reported in Caucasians. The allelic frequency of V368I is 0.70 in Japan and 0.51 in southern European populations. Viral-associated encephalopathy is characterized by a high-grade fever accompanied within 12 to 48 hours by febrile convulsions, often leading to coma, multiple-organ failure, and high morbidity and mortality. {6:Chen et al. (2005)} concluded that their findings suggest that a continuous high-grade fever, often accompanied by fasting, causes a systemic and metabolic energy crisis in patients with thermolabile polymorphic variations in the CPT2 gene. In vitro studies by {34:Yao et al. (2008)} demonstrated that the F352C/V368I variant proteins exerted a dominant-negative effect on the CPT2 homotetramer and had shortened half-lives compared to wildtype, consistent with intracellular instability. The studies also confirmed thermolability, with attenuated CPT2 activity associated with decreased ATP levels at higher temperatures. {34:Yao et al. (2008)} hypothesized that ATP depletion may cause increased blood-brain barrier permeability and contribute to cerebral edema in affected individuals. Among 29 Japanese patients with infection-induced acute encephalopathy, {20:Shinohara et al. (2011)} found significantly higher frequency of the 352C variant in exon 4 of the CPT2 gene compared to controls (27.6 vs 13.5%, odds ratio of 2.44, p = 0.011). All patients with 352C had the 368I allele and the 647M allele (CIM haplotype). There was no difference in allele frequency between patients with a clinical diagnosis of acute necrotizing encephalopathy and those with acute encephalopathy with biphasic seizures and late reduced diffusion, and there was no correlation between good and poor prognosis. {15:Mak et al. (2011)} reported 2 unrelated Chinese boys from Hong Kong with fatal virally-induced acute encephalopathy. Both were heterozygous for F352C and homozygous for V368I. The infectious agents were Coxsackie virus group A in 1 patient and influenza A, subtype H1 in the other. Both patients had high fever, seizures, and rapid deterioration with cerebral edema and multiorgan failure. Plasma acylcarnitines were increased in all mutation carriers, including asymptomatic parents. mutations CPT2, PHE352CYS AND VAL368ILE number 18 clinvarAccessions RCV000078115;;1;;;RCV000078116;;1;;;RCV000023026;;1;;;RCV000124601;;1 prefix * titles alternativeTitles CPT II preferredTitle CARNITINE PALMITOYLTRANSFERASE II; CPT2 textSectionList textSection textSectionTitle Description textSectionContent The CPT2 gene encodes carnitine palmitoyltransferase II, an enzyme that participates in fatty acid oxidation. The carnitine palmitoyltransferase (CPT; {EC 2.3.1.21}) enzyme system, in conjunction with acyl-CoA synthetase and carnitine/acylcarnitine translocase ({613698}), provides the mechanism whereby long-chain fatty acids are transferred from the cytosol to the mitochondrial matrix to undergo beta-oxidation. The CPT I isozymes (see CPT1A; {600528} and CPT1B; {601987}) are located in the mitochondrial outer membrane and are detergent-labile, whereas CPT II is located in the inner mitochondrial membrane and is detergent-stable ({3:Bieber, 1988}). textSectionName description textSectionTitle Cloning textSectionContent By screening a human liver cDNA library, {10:Finocchiaro et al. (1991)} cloned and sequenced a cDNA encoding human carnitine palmitoyltransferase II. The deduced 658-amino acid protein contains a 25-residue NH2-terminal leader peptide. The amino acid sequence shows 82.2% homology with the rat CTP II protein. {18:Montermini et al. (1994)} identified regulatory elements in the promoter of the CPT2 gene. textSectionName cloning textSectionTitle Gene Structure textSectionContent {28:Verderio et al. (1995)} determined that the CPT2 gene contains 5 exons spanning approximately 20 kb of DNA. textSectionName geneStructure textSectionTitle Mapping textSectionContent By human-hamster somatic cell hybridization, {10:Finocchiaro et al. (1991)} assigned the CPT2 gene (which they referred to as CPT1) to chromosome 1pter-q12. By fluorescence in situ hybridization, {17:Minoletti et al. (1992)} refined the assignment of the CPT2 gene to 1p13-p11. However, also using fluorescence in situ hybridization, {11:Gellera et al. (1994)} concluded that the CPT2 gene is located in band 1p32 and that the previously used probe that mapped the gene to 1p13-p11 'must be considered an as yet anonymous probe.' It is now clear that the gene mapped to chromosome 1p32 was CPT2. textSectionName mapping textSectionTitle Gene Function textSectionContent {5:Britton et al. (1995)} distinguished CPT I and CPT II, and reported that major control over the fatty acid oxidation process is exerted at the level of CPT I by the unique inhibition of this enzyme by malonyl-CoA. {21:Slama et al. (1996)} carried out complementation experiments between cell lines derived from patients with CPT I deficiency ({255120}) or infantile CPT II deficiency ({600649}) by measuring restoration of tritium release from palmitate. As expected, no complementation was observed in heteropolykaryons resulting from fusion of CPT I-deficient cells or of CPT II-deficient cells. Conversely, complementation was observed in fusions of CPT I- and CPT II-deficient cells. These data suggested that the defects in CPT I deficiency and infantile CPT II deficiency are determined by mutations in distinct genes. Palmitate oxidation by control or CPT I-deficient cell lines decreased when these cell lines were cocultured with infantile CPT II-deficient cell lines. This effect, not observed in a coculture with an adult CPT II-deficient cell line, was suppressed by a high carnitine concentration. textSectionName geneFunction textSectionTitle Nomenclature textSectionContent {10:Finocchiaro et al. (1991)}, {17:Minoletti et al. (1992)}, and {11:Gellera et al. (1994)} all referred to the CPT gene on chromosome 1 as CPT1; it is referred to here as CPT2 following the elucidation by {5:Britton et al. (1995)}. CPT1 ({600528}) maps to chromosome 11. textSectionName nomenclature textSectionTitle Molecular Genetics textSectionContent Carnitine Palmitoyltransferase II Deficiency In a patient with infantile carnitine palmitoyltransferase II deficiency ({600649}) with hypoketotic hypoglycemia and cardiomyopathy, {26:Taroni et al. (1992)} identified a homozygous mutation in the CPT2 gene ({600650.0001}). The patient was also homozygous for a mutant CPT2 allele (termed the 'ICV' allele) that carried 2 other rare polymorphisms. In a patient with infantile CPT II deficiency reported by {7:Demaugre et al. (1991)}, {4:Bonnefont et al. (1996)} identified a homozygous mutation in the CPT2 gene ({600650.0005}). In a Dutch patient with adult-onset CPT II deficiency ({255110}), {25:Taroni et al. (1993)} identified compound heterozygosity for 2 mutations in the CPT2 gene ({600650.0001}; {600650.0002}). {9:Elpeleg et al. (2001)} reported 2 Ashkenazi Jewish sibs with the antenatal, or lethal neonatal, form of CPT II deficiency ({608836}) who were homozygous for an allele carrying 2 mutations in exon 4 of the CPT2 gene ({600650.0009}). {14:Isackson et al. (2008)} identified compound heterozygous or homozygous mutations in the CPT2 gene in 3 patients with lethal neonatal CPT II deficiency (see, e.g., {600650.0013}) and in 2 patients with infantile CPT II deficiency. Three of the mutations were novel (see, e.g., {600650.0017}). Infection-Induced Acute Encephalopathy-4 {6:Chen et al. (2005)} found that a Japanese girl with fatal infection-induced acute encephalopathy-4 (IIAE4; {614212}) was heterozygous for a thermolabile allele in the CPT2 gene ({600650.0018}). She had significantly increased serum acylcarnitine levels during febrile convulsions. Her 2 unaffected brothers, who were heterozygous for the allele, and their father, who was homozygous for the allele, had slightly increased serum acylcarnitine compared to normal values in the nonfebrile state. The mother, who was heterozygous only for the 368I, had normal acylcarnitine levels in the nonfebrile state. textSectionName molecularGenetics textSectionTitle Genotype/Phenotype Correlations textSectionContent In a study of 19 patients with CPT II deficiency, 13 with adult onset and 6 with infantile onset, {27:Thuillier et al. (2003)} found that all patients with the infantile form had mutations in exon 4 or 5 of the CPT2 gene. Twelve of the adult patients carried the S113L ({600650.0002}) mutation. Although there was an overlap in residual CPT II activity between the 2 groups (ranging from 4 to 12%), there was a significant decrease in palmitate oxidation in the infantile group (less than 10%) compared to the adult group (45 to 70%). {27:Thuillier et al. (2003)} concluded that both the type and location of CPT2 mutations and at least 1 additional, unidentified genetic factor modulate the long-chain fatty acid flux and therefore the severity of the disease. {19:Orngreen et al. (2005)} identified 2 unrelated patients with mild features of late-onset CPT II deficiency who each carried a single mutation in the CPT2 gene ({600650.0015} and {600650.0016}). The findings indicated that some heterozygous CPT2 mutation carriers may be symptomatic. textSectionName genotypePhenotypeCorrelations geneMapExists true editHistory carol : 04/22/2013 alopez : 3/20/2013 terry : 12/21/2012 mgross : 10/5/2012 terry : 10/10/2011 carol : 10/3/2011 ckniffin : 9/19/2011 terry : 4/7/2011 carol : 1/19/2011 wwang : 4/20/2009 ckniffin : 4/9/2009 wwang : 12/7/2007 ckniffin : 12/3/2007 wwang : 5/13/2005 ckniffin : 5/10/2005 carol : 8/25/2004 carol : 8/23/2004 ckniffin : 8/19/2004 terry : 8/10/2004 tkritzer : 6/24/2003 terry : 6/11/2003 carol : 2/20/2003 carol : 2/20/2003 tkritzer : 2/12/2003 terry : 2/11/2003 alopez : 10/8/2002 carol : 8/31/2001 mcapotos : 8/24/2001 cwells : 2/21/2001 terry : 2/15/2001 alopez : 10/25/1999 terry : 9/24/1999 carol : 5/18/1999 alopez : 10/26/1998 carol : 10/26/1998 psherman : 3/27/1998 dholmes : 3/6/1998 mark : 6/19/1996 terry : 6/11/1996 terry : 5/3/1996 terry : 4/30/1996 terry : 3/4/1996 terry : 3/4/1996 mark : 3/4/1996 mark : 3/4/1996 mark : 3/4/1996 mark : 3/4/1996 mark : 3/4/1996 terry : 2/20/1996 mimadm : 11/3/1995 mark : 7/26/1995 dateCreated Wed, 26 Jul 1995 03:00:00 EDT creationDate Victor A. McKusick : 7/26/1995 epochUpdated 1366614000 dateUpdated Mon, 22 Apr 2013 03:00:00 EDT referenceList reference articleUrl http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=11389301 publisherName HighWire Press title Detection of neonatal carnitine palmitoyltransferase II deficiency by expanded newborn screening with tandem mass spectrometry. mimNumber 600650 referenceNumber 1 publisherAbbreviation HighWire pubmedID 11389301 source Pediatrics 107: E103, 2001. Note: Electronic Article. authors Albers, S., Marsden, D., Quackenbush, E., Stark, A. R., Levy, H. L., Irons, M. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=17709715 publisherName HighWire Press title A Japanese adult form of CPT II deficiency associated with a homozygous F383Y mutation. mimNumber 600650 referenceNumber 2 publisherAbbreviation HighWire pubmedID 17709715 source Neurology 69: 804-805, 2007. authors Aoki, J., Yasuno, T., Sugie, H., Kido, H., Nishino, I., Shigematsu, Y., Kanazawa, M., Takayanagi, M., Kumami, M., Endo, K., Kaneoka, H., Yamaguchi, M., Fukuda, T., Yamamoto, T. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://arjournals.annualreviews.org/doi/full/10.1146/annurev.bi.57.070188.001401?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Carnitine. mimNumber 600650 referenceNumber 3 publisherAbbreviation ATYPON pubmedID 3052273 source Annu. Rev. Biochem. 57: 261-283, 1988. authors Bieber, L. L. pubmedImages false publisherUrl http://www.atypon.com/ title Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. mimNumber 600650 referenceNumber 4 pubmedID 8651281 source Am. J. Hum. Genet. 58: 971-978, 1996. authors Bonnefont, J.-P., Taroni, F., Cavadini, P., Cepanec, C., Brivet, M., Saudubray, J.-M., Leroux, J.-P., Demaugre, F. pubmedImages false articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7892212 publisherName HighWire Press title Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene. mimNumber 600650 referenceNumber 5 publisherAbbreviation HighWire pubmedID 7892212 source Proc. Nat. Acad. Sci. 92: 1984-1988, 1995. authors Britton, C. H., Schultz, R. A., Zhang, B., Esser, V., Foster, D. W., McGarry, J. D. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0014-5793(05)00282-6 publisherName Elsevier Science title Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy. mimNumber 600650 referenceNumber 6 publisherAbbreviation ES pubmedID 15811315 source FEBS Lett. 579: 2040-2044, 2005. authors Chen, Y., Mizuguchi, H., Yao, D., Ide, M., Kuroda, Y., Shigematsu, Y., Yamaguchi, S., Yamaguchi, M., Kinoshita, M., Kido, H. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI115090 publisherName Journal of Clinical Investigation title Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death: physiopathological approach to carnitine palmitoyltransferase II deficiencies. mimNumber 600650 referenceNumber 7 publisherAbbreviation JCI pubmedID 1999498 source J. Clin. Invest. 87: 859-864, 1991. authors Demaugre, F., Bonnefont, J.-P., Colonna, M., Cepanec, C., Leroux, J.-P., Saudubray, J.-M. pubmedImages false publisherUrl http://www.jci.org title Muscle carnitine palmityltransferase deficiency: a case with enzyme deficiency in cultured fibroblasts. mimNumber 600650 referenceNumber 8 pubmedID 736528 source Ann. Neurol. 4: 465-467, 1978. authors DiDonato, S., Cornelio, F., Pacini, L., Peluchetti, D., Rimoldi, M., Spreafico, S. pubmedImages false articleUrl http://dx.doi.org/10.1002/ajmg.1457 publisherName John Wiley & Sons, Inc. title Antenatal presentation of carnitine palmitoyltransferase II deficiency. mimNumber 600650 referenceNumber 9 publisherAbbreviation Wiley pubmedID 11477613 source Am. J. Med. Genet. 102: 183-187, 2001. authors Elpeleg, O. N., Hammerman, C., Saada, A., Shaag, A., Golzand, E., Hochner-Celnikier, D., Berger, I., Nadjari, M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1988962 publisherName HighWire Press title cDNA cloning, sequence analysis, and chromosomal localization of the gene for human carnitine palmitoyltransferase. mimNumber 600650 referenceNumber 10 publisherAbbreviation HighWire pubmedID 1988962 source Proc. Nat. Acad. Sci. 88: 661-665, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 10981 only, 1991. authors Finocchiaro, G., Taroni, F., Rocchi, M., Liras Martin, A., Colombo, I., Tarelli, G. T., DiDonato, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(84)71605-3 publisherName Elsevier Science title Assignment of the human carnitine palmitoyltransferase II gene (CPT1) to chromosome 1p32. mimNumber 600650 referenceNumber 11 publisherAbbreviation ES pubmedID 7896283 source Genomics 24: 195-197, 1994. authors Gellera, C., Verderio, E., Floridia, G., Finocchiaro, G., Montermini, L., Cavadini, P., Zuffardi, O., Taroni, F. pubmedImages false publisherUrl http://www.elsevier.com/ source Am. J. Hum. Genet. 51 (suppl.): A168 only, 1992. mimNumber 600650 authors Gellera, C., Witt, D. R., Verderio, E., Cavadini, P., DiDonato, S., Taroni, F. title Molecular study of lethal neonatal carnitine palmitoyltransferase II (CPT II) deficiency. (Abstract) referenceNumber 12 articleUrl http://link.springer.de/link/service/journals/00439/bibs/6097003/60970291.htm publisherName Springer title Inheritance of the S113L mutation within an inbred family with carnitine palmitoyltransferase enzyme deficiency. mimNumber 600650 referenceNumber 13 publisherAbbreviation Springer pubmedID 8786066 source Hum. Genet. 97: 291-293, 1996. authors Handig, I., Dams, E., Taroni, F., Van Laere, S., de Barsy, T., Willems, P. J. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(08)00145-5 publisherName Elsevier Science title CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. mimNumber 600650 referenceNumber 14 publisherAbbreviation ES pubmedID 18550408 source Molec. Genet. Metab. 94: 422-427, 2008. authors Isackson, P. J., Bennett, M. J., Lichter-Konecki, U., Willis, M., Nyhan, W. L., Sutton, V. R., Tein, I., Vladutiu, G. D. pubmedImages false publisherUrl http://www.elsevier.com/ title Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants. mimNumber 600650 referenceNumber 15 pubmedID 21697855 source J. Hum. Genet. 56: 617-621, 2011. authors Mak, C. M., Lam, C., Fong, N., Siu, W., Lee, H. H., Siu, T., Lai, C., Law, C., Tong, S., Poon, W., Lam, D. S., Ng, H, Yuen, Y., Tam, S., Que, T., Kwong, N., Chan, A. Y. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1097-4598(199907)22:7<941::AID-MUS20>3.0.CO;2-Z publisherName John Wiley & Sons, Inc. title Molecular analysis in Spanish patients with muscle carnitine palmitoyltransferase deficiency. mimNumber 600650 referenceNumber 16 publisherAbbreviation Wiley pubmedID 10398215 source Muscle Nerve 22: 941-943, 1999. authors Martin, M. A., Rubio, J. C., De Bustos, F., Del Hoyo, P., Campos, Y., Garcia, A., Bornstein, B., Cabello, A., Arenas, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Localization of the human gene for carnitine palmitoyltransferase to 1p13-p11 by nonradioactive in situ hybridization. mimNumber 600650 referenceNumber 17 pubmedID 1339389 source Genomics 13: 1372-1374, 1992. Note: Retraction: Genomics 24: 198 only, 1994. authors Minoletti, F., Colombo, I., Liras Martin, A., DiDonato, S., Taroni, F., Finocchiaro, G., Pandolfo, M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0167-4781(94)90280-1 publisherName Elsevier Science title Identification of 5-prime regulatory regions of the human carnitine palmitoyltransferase II gene. mimNumber 600650 referenceNumber 18 publisherAbbreviation ES pubmedID 8086471 source Biochim. Biophys. Acta 1219: 237-240, 1994. authors Montermini, L., Wang, H., Verderio, E., Taroni, F., DiDonato, S., Finocchiaro, G pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ana.20320 publisherName John Wiley & Sons, Inc. title Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations. mimNumber 600650 referenceNumber 19 publisherAbbreviation Wiley pubmedID 15622536 source Ann. Neurol. 57: 60-66, 2005. authors Orngreen, M. C., Duno, M., Ejstrup, R., Christensen, E., Schwartz, M., Sacchetti, M., Vissing, J. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0387-7604(10)00230-5 publisherName Elsevier Science title Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases. mimNumber 600650 referenceNumber 20 publisherAbbreviation ES pubmedID 20934285 source Brain Dev. 33: 512-517, 2011. authors Shinohara, M., Saitoh, M., Takanashi, J., Yamanouchi, H., Kubota, M., Goto, T., Kikuchi, M., Shiihara, T., Yamanaka, G., Mizuguchi, M. pubmedImages false publisherUrl http://www.elsevier.com/ title Complementation analysis of carnitine palmitoyltransferase I and II defects. mimNumber 600650 referenceNumber 21 pubmedID 8888280 source Pediat. Res. 40: 542-546, 1996. authors Slama, A., Brivet, M., Boutron, A., Legrand, A., Saudubray, J.-M., Demaugre, F. pubmedImages false title A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency. mimNumber 600650 referenceNumber 22 pubmedID 12560872 source J. Hum. Genet. 48: 8-13, 2003. authors Smeets, R. J. P., Smeitink, J. A. M., Semmekrot, B. A., Scholte, H. R., Wanders, R. J. A., van den Heuvel, L. P. W. J. pubmedImages false articleUrl http://dx.doi.org/10.1002/(SICI)1098-1004(1999)13:3<210::AID-HUMU5>3.0.CO;2-0 publisherName John Wiley & Sons, Inc. title Novel mutations associated with carnitine palmitoyltransferase II deficiency. mimNumber 600650 referenceNumber 23 publisherAbbreviation Wiley pubmedID 10090476 source Hum. Mutat. 13: 210-220, 1999. authors Taggart, R. T., Smail, D., Apolito, C., Vladutiu, G. D. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source Am. J. Hum. Genet. 55 (suppl.): A245 only, 1994. mimNumber 600650 authors Taroni, F., Gellera, C., Cavadini, P., Baratta, S., Lamantea, E., Dethlefs, S., DiDonato, S., Reik, R. A., Benke, P. J. title Lethal carnitine palmitoyltransferase (CPT) II deficiency in newborns: a molecular-genetic study. (Abstract) referenceNumber 24 articleUrl http://dx.doi.org/10.1038/ng0793-314 publisherName Nature Publishing Group title Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. mimNumber 600650 referenceNumber 25 publisherAbbreviation NPG pubmedID 8358442 source Nature Genet. 4: 314-320, 1993. authors Taroni, F., Verderio, E., Dworzak, F., Willems, P. J., Cavadini, P., DiDonato, S. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1528846 publisherName HighWire Press title Molecular characterization of inherited carnitine palmitoyltransferase II deficiency. mimNumber 600650 referenceNumber 26 publisherAbbreviation HighWire pubmedID 1528846 source Proc. Nat. Acad. Sci. 89: 8429-8433, 1992. authors Taroni, F., Verderio, E., Fiorucci, S., Cavadini, P., Finocchiaro, G., Uziel, G., Lamantea, E., Gellera, C., DiDonato, S. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/humu.10201 publisherName John Wiley & Sons, Inc. title Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency. mimNumber 600650 referenceNumber 27 publisherAbbreviation Wiley pubmedID 12673791 source Hum. Mutat. 21: 493-501, 2003. authors Thuillier, L., Rostane, H., Droin, V., Demaugre, F., Brivet, M., Kadhom, N., Prip-Buus, C., Gobin, S., Saudubray, J.-M., Bonnefont, J.-P. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7711730 publisherName HighWire Press title Carnitine palmitoyltransferase II deficiency: structure of the gene and characterization of two novel disease-causing mutations. mimNumber 600650 referenceNumber 28 publisherAbbreviation HighWire pubmedID 7711730 source Hum. Molec. Genet. 4: 19-29, 1995. authors Verderio, E., Cavadini, P., Montermini, L., Wang, H., Lamantea, E., Finocchiaro, G., DiDonato, S., Gellera, C., Taroni, F. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/S1096-7192(00)93009-9 publisherName Elsevier Science title A variable myopathy associated with heterozygosity for the R503C mutation in the carnitine palmitoyltransferase II gene. mimNumber 600650 referenceNumber 29 publisherAbbreviation ES pubmedID 10873395 source Molec. Genet. Metab. 70: 134-141, 2000. authors Vladutiu, G. D., Bennett, M. J., Smail, D., Wong, L.-J., Taggart, R. T., Lindsley, H. B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(02)00196-8 publisherName Elsevier Science title Lethal neonatal and severe late infantile forms of carnitine palmitoyltransferase II deficiency associated with compound heterozygosity for different protein truncation mutations. mimNumber 600650 referenceNumber 30 publisherAbbreviation ES pubmedID 12410208 source J. Pediat. 141: 734-736, 2002. authors Vladutiu, G. D., Quackenbush, E. J., Hainline, B. E., Albers, S., Smail, D. S., Bennett, M. J. pubmedImages false publisherUrl http://www.elsevier.com/ source Am. J. Hum. Genet. 63 (suppl.): A5 only, 1998. mimNumber 600650 authors Vladutiu, G. D., Taggart, R. T., Smail, D., Lindsley, H. B., Hogan, K. title A carnitine palmitoyl transferase II (CPT2) arg503cys mutation confers malignant hyperthermia and variable myopathy. (Abstract) referenceNumber 31 source Am. J. Hum. Genet. 49 (suppl.): A109 only, 1991. mimNumber 600650 authors Witt, S. R., Theobald, M., Santa-Maria, M., Packman, S., Townsend, S., Sweetman, L., Goodman, S., Rhead, W., Hoppel, C. title Carnitine palmitoyl transferase-type 2 deficiency: two new cases and successful prenatal diagnosis. (Abstract) referenceNumber 32 articleUrl http://link.springer.de/link/service/journals/00439/bibs/6098001/60980116.htm publisherName Springer title Two novel gene mutations (glu174-to-lys, phe383-to-tyr) causing the 'hepatic' form of carnitine palmitoyltransferase II deficiency. mimNumber 600650 referenceNumber 33 publisherAbbreviation Springer pubmedID 8682496 source Hum. Genet. 98: 116-118, 1996. authors Yamamoto, S., Abe, H., Kohgo, T., Ogawa, A., Ohtake, A., Hayashibe, H., Sakuraba, H., Suzuki, Y., Aramaki, S., Takayanagi, M., Hasegawa, S., Niimi, H. pubmedImages false publisherUrl http://www.springeronline.com/ articleUrl http://dx.doi.org/10.1002/humu.20717 publisherName John Wiley & Sons, Inc. title Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy. mimNumber 600650 referenceNumber 34 publisherAbbreviation Wiley pubmedID 18306170 source Hum. Mutat. 29: 718-727, 2008. authors Yao, D., Mizuguchi, H., Yamaguchi, M., Yamada, H., Chida, J., Shikata, K., Kido, H. pubmedImages false publisherUrl http://www.interscience.wiley.com/ externalLinks cmgGene false mgiHumanDisease false hprdIDs 02802 nbkIDs NBK1253;;Carnitine Palmitoyltransferase II Deficiency refSeqAccessionIDs NG_008035.1 uniGenes Hs.713535 approvedGeneSymbols CPT2 nextGxDx true flybaseIDs FBgn0035383 dermAtlas false umlsIDs C1413690 gtr true geneIDs 1376 swissProtIDs P23786 zfinIDs ZDB-GENE-030131-6719 ensemblIDs ENSG00000157184,ENST00000371486 geneTests true mgiIDs MGI:109176 ncbiReferenceSequences 169790951,530361830 ordrDiseases 1121;;Carnitine palmitoyl transferase 2 deficiency genbankNucleotideSequences 298532106,18135127,507073,1086454,1041191,164690489,33870376,511871439,298547814,74230049,298538853,23296310,148117420,33876697,45822981,180988,62897664 proteinSequences 298532107,416836,1041195,1041193,13477387,579811,4503023,298547815,298538854,119627158,530361831,45822982,189053401,62897665,12803261,180989 geneticsHomeReferenceIDs gene;;CPT2;;CPT2

entryList

entry status live allelicVariantExists true epochCreated 943344000 geneMap geneSymbols CST3, ARMD11 sequenceID 13558 phenotypeMapList phenotypeMap phenotypeMappingKey 3 mimNumber 604312 phenotypeInheritance Autosomal dominant phenotype Cerebral amyloid angiopathy phenotypeMimNumber 105150 phenotypeMimNumber 611953 mimNumber 604312 phenotypeInheritance None phenotypicSeriesMimNumber 603075 phenotypeMappingKey 3 phenotype Macular degeneration, age-related, 11 chromosomeLocationStart 23608533 chromosomeSort 123 chromosomeSymbol 20 mimNumber 604312 geneInheritance None confidence C mappingMethod REa, A geneName Cystatin C comments proximal to 20p11.2 mouseMgiID MGI:102519 mouseGeneSymbol Cst3 computedCytoLocation 20p11.21 cytoLocation 20p11.2 transcript uc002wtn.1 chromosomeLocationEnd 23618684 chromosome 20 contributors Jane Kelly - updated : 4/15/2008 Cassandra L. Kniffin - updated : 1/7/2008 Victor A. McKusick - updated : 12/20/2007 Cassandra L. Kniffin - updated : 4/12/2006 Cassandra L. Kniffin - reorganized : 12/5/2005 Cassandra L. Kniffin - updated : 12/1/2005 Victor A. McKusick - updated : 12/29/2004 Victor A. McKusick - updated : 11/24/1999 externalLinks mgiIDs MGI:102519 mgiHumanDisease false nextGxDx false ncbiReferenceSequences 530425631,568599816 refSeqAccessionIDs NG_012887.2 dermAtlas false hprdIDs 05056 swissProtIDs P01034 zfinIDs ZDB-GENE-030131-373 uniGenes Hs.304682 gtr true cmgGene false ensemblIDs ENSG00000101439,ENST00000376925 umlsIDs C1413772 genbankNucleotideSequences 164689616,30369,83406522,30371,148175984,30582516,181385,511788525,123981071,259423736,74230018,49456988,30257,49456928,34366680,82571742,15341821,9944239,157928177,11592810,148175983,325651799,30367,388979760 geneTests true approvedGeneSymbols CST3 geneIDs 1471 proteinSequences 83406523,4490944,118183,296643,30582517,4503107,181387,119630543,259423737,119630542,49456989,325651800,189053333,755738,49456929,123981072,15341822,82571743,157928178,568599832 geneticsHomeReferenceIDs gene;;CST3;;CST3 clinicalSynopsisExists false mimNumber 604312 allelicVariantList allelicVariant status live name AMYLOIDOSIS, CEREBROARTERIAL, ICELANDIC TYPE dbSnps rs28939068 text In patients with Icelandic-type cerebroarterial amyloidosis ({105150}), {3:Abrahamson et al. (1987)} identified a 358T-A transversion in the CST3 gene, resulting in a leu68-to-gln (L68Q) substitution. {40:Palsdottir et al. (1988)} used restriction site analysis to show that the L68Q mutation segregated with the disorder in 8 families. {5:Abrahamson et al. (1992)} described a rapid and simple method of diagnosis of Icelandic-type cerebroarterial amyloidosis based on oligonucleotide-directed enzymatic amplification of a 275-bp genomic DNA segment containing exon 2 of the cystatin C gene from a blood sample, followed by digestion of the amplification product with AluI. Loss of an AluI recognition site in the amplified DNA segment from patients resulted in a deviating band-pattern on agarose gel electrophoresis. Affected members of 4 different families all had the L68Q mutation. Using in vitro functional analysis, {2:Abrahamson and Grubb (1994)} found that mutant L68Q cystatin C protein effectively inhibited the cysteine protease cathepsin B ({116810}), but started to dimerize and lose biologic activity immediately after it was transferred to a nondenaturing buffer. The dimerization was highly temperature-dependent, with a rise in incubation temperature from 37 to 40 degrees centigrade resulting in a 150% increase in dimerization rate. The aggregation at physiologic concentrations was increased at 40 degrees compared to 37 degrees C, by approximately 60%. {2:Abrahamson and Grubb (1994)} suggested that medical intervention to abort febrile periods in carriers of the disease trait might reduce the in vivo formation of L68Q cystatin C aggregates. mutations CST3, LEU68GLN number 1 clinvarAccessions RCV000005988;;1 status live name MACULAR DEGENERATION, AGE-RELATED, 11 dbSnps rs1064039 text In a case-control study, {46:Zurdel et al. (2002)} investigated whether haplotypes A or B (A25T) of CST3 were genetically associated with exudative age-related macular degeneration ({611953}) in a Caucasian population. There was a significant difference in genotype counts between patients and controls, which could be explained completely by an excess of the homozygous CST3 genotype B/B in patients (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI, 1.28-6.86). {46:Zurdel et al. (2002)} concluded that A25T may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. mutations CST3, ALA25THR number 2 clinvarAccessions RCV000005989;;1 prefix * titles alternativeTitles CYSTATIN C;; GAMMA-TRACE preferredTitle CYSTATIN 3; CST3 textSectionList textSection textSectionTitle Description textSectionContent Cystatin C, which belongs to the type II cystatin gene family, is a potent inhibitor of lysosomal proteinases ({41:Pirttila et al., 2005}). textSectionName description textSectionTitle Cloning textSectionContent {22:Grubb and Lofberg (1982)} reported the amino acid sequence of cystatin C, which they referred to as 'gamma-trace,' isolated from human urine. It is a single 120-residue polypeptide with a molecular mass of approximately 13.26 kD. The protein is constitutively secreted shortly after synthesis ({8:Barrett et al., 1984}; {35:Merz et al., 1997}). {3:Abrahamson et al. (1987)} isolated recombinant cystatin C-producing clones from a human placenta lambda-gt11 cDNA library. One of the clones encoded a 120-amino acid complete mature cystatin C protein with a 26-residue hydrophobic leader sequence, suggesting an extracellular function. The deduced protein sequence confirmed the protein sequence of cystatin C isolated from human urine. {1:Abrahamson (1988)} reported the isolation and characterization of 6 human cysteine proteinase inhibitors, including cystatin C. Whereas cystatins D ({123858}), S ({123857}), and SA ({123856}) are expressed primarily in salivary glands, cystatin C is expressed in virtually all organs of the body. According to its high concentration in biologic fluids, the authors concluded that cystatin C is probably one of the most important extracellular inhibitors of cysteine proteases. textSectionName cloning textSectionTitle Gene Structure textSectionContent {6:Abrahamson et al. (1990)} determined that the CST3 gene contains 3 exons and spans 4.3 kb. {25:Huh et al. (1995)} determined the structure of the mouse Cst3 gene by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of the 5-prime flanking region and 1.7 kb of the 3-prime flanking region. The sequence revealed an overall organization very similar to that of the human CST3 gene. textSectionName geneStructure textSectionTitle Mapping textSectionContent By human-rodent somatic cell hybridizations, {4:Abrahamson et al. (1989)} mapped the human CST3 to chromosome 20. Using Southern blot analysis, pulsed field gel electrophoresis (PFGE), and both radioactive and fluorescence in situ hybridization, {20:Gopal Rao et al. (1991)} confirmed the assignment of CST3 and the other family II cystatins to chromosome 20. PFGE with a cystatin-C-specific probe showed a single 300-kb BssHII fragment and in situ hybridization mapped the locus specifically to 20p11. This location was found to be proximal to the breakpoint in a patient with Alagille syndrome (see {118450}). From the results of fluorescence in situ hybridization, Southern blot, and PFGE studies, {43:Schnittger et al. (1993)} concluded that CST3 and probably 7 other members of the cystatin gene family are clustered within a 1.2-Mb segment on chromosome 20p11.2. By fluorescence in situ hybridization, {15:Dickinson et al. (1994)} showed that the cystatin gene cluster (CST1 to 5, CST1 and 2 pseudogenes) spans less than 905 kb. {25:Huh et al. (1995)} mapped the mouse Cst3 gene to distal mouse chromosome 2. textSectionName mapping textSectionTitle Gene Function textSectionContent Cystatin C, which was first referred to as 'gamma-trace,' was originally described as a constituent of normal cerebrospinal fluid (CSF) and of urine from patients with renal failure ({22:Grubb and Lofberg, 1982}). It is present in a number of neuroendocrine cells and its concentration in the CSF was reported to be 5.5 times that in plasma of healthy adults ({32:Lofberg and Grubb, 1979}; {34:Lofberg et al., 1981}; {31:Lofberg et al., 1983}). {22:Grubb and Lofberg (1982)} detected the protein in human pituitary gland, and suggested that it is part of the gastroenteropancreatic neuroendocrine system. The pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA; {100070}) involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S (CTSS; {116845}) and K (CTSK; {601105}), are overexpressed at sites of arterial elastin damage. In both atherosclerotic and aneurysmal aortic lesions, {44:Shi et al. (1999)} found a severe reduction in cystatin C levels compared to normal vascular wall smooth muscle cells. Among 122 AAA patients screened by ultrasonography, increased abdominal aortic diameter correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular smooth muscle cells secreted cathepsins whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta-1 ({190180}). These findings highlighted a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and established that cystatin C deficiency occurs in vascular disease. {44:Shi et al. (1999)} stated that the marked suppression of cystatin C concurrent with augmented expression of cysteine proteases observed in their studies represented the first acquired cysteine protease inhibitor deficiency in human disease. {41:Pirttila et al. (2005)} found increased cystatin C expression in the glial cells in the molecular layer of the hippocampal dentate gyrus in brain tissue from 61 patients with temporal lobe epilepsy (see, e.g., {608096}) who underwent epilepsy surgery. The findings were most pronounced in 26 patients with hippocampal sclerosis and in those with granule cell dispersion. High cystatin C expression was also associated with abnormal migration of newborn neuronal cells. Similar findings were observed in rat models of chronic epilepsy. {41:Pirttila et al. (2005)} concluded that cystatin C is involved in network reorganization in the epileptic dentate gyrus. In CSF samples from 19 of 29 patients with multiple sclerosis (MS; {126200}), {26:Irani et al. (2006)} identified a 12.5-kD cleavage product of cystatin C formed by the removal of the last 8 amino acids from the C terminus. The 12.5-kD peak was not identified in CSF samples from 27 patients with unrelated neurologic disorders or 27 additional patients with acute transverse myelitis, but lower levels than that of MS patients were found in some patients with HIV infection. {26:Irani et al. (2006)} suggested that cleavage of cystatin C may be an adaptive host response. {14:Del Boccio et al. (2007)} and {23:Hansson et al. (2007)} independently identified a 12.5-kD product of cystatin C that is formed by degradation of the first 8 N-terminal amino acids resulting from inappropriate storage at -20 degrees Celsius. Compared to controls, no significant differences in cystatin C fragments were observed in the CSF of 21 and 43 MS patients, respectively. Both groups concluded that CSF cystatin C is not a useful marker for the diagnosis of MS. In a response, {45:Wheeler et al. (2007)} stated that they had stored the CSF samples at -80 degrees Celsius ({26:Irani et al., 2006}), and that the cleavage site identified by them was at the C-terminal. A more accurate measurement indicated that the C-terminal fragment was 12,546.6 Da and the N-terminal fragment was 12,561.3 Da, suggesting that there are 2 similarly sized, yet distinct fragments of cystatin C. textSectionName geneFunction textSectionTitle Molecular Genetics textSectionContent {7:Balbin and Abrahamson (1991)} identified 3 variants within an 85-bp segment in the promoter region of the CST3 gene. All 3 were on the same allele and displayed mendelian inheritance. The polymorphisms were apparently linked, since alleles carrying only 1 of the 3 base changes were not identified. The variant allele, termed 'B,' had a frequency of 0.29 ('A' had a frequency of 0.71). The 3 polymorphisms result in 2 commonly found haplotypes: 'A,' comprising -157G, -72A, and +73G, and 'B,' comprising -157C, -72C, and +73A ({39:Olafsson, 1995}; {16:Finckh et al., 2000}). Cerebroarterial Amyloidosis, Icelandic Type Using high performance liquid chromatography (HPLC) tryptic fingerprint analyses, {17:Ghiso et al. (1986)} found differences between normal cystatin C and a cystatin C variant in Icelandic amyloidosis ({105150}), which is also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA). In a patient with HCHWA, {3:Abrahamson et al. (1987)} identified a mutation in the CST3 gene (L68Q; {604312.0001}). {28:Jensson et al. (1987)} found abnormal cystatin C protein sequences in the amyloid protein deposited in patients with Icelandic-type amyloidosis. Abnormalities included absence of 10 amino acids from the amino terminal and an amino acid substitution at position 58, which corresponded to position 68 in cystatin C. Alzheimer Disease By linkage analysis, {10:Blacker et al. (1997)} and {19:Goddard et al. (2004)} identified a susceptibility locus for late-onset Alzheimer disease (AD8; {607116}) in an 11.8-cM candidate region on chromosome 20 containing the CST3 gene. {19:Goddard et al. (2004)} observed an association between AD and markers located near the CST3 gene. Among 517 AD patients, {16:Finckh et al. (2000)} found that homozygosity for the CST3 B haplotype was significantly associated with late-onset AD (odds ratio of 3.8). {13:Crawford et al. (2000)} found an association between the +73G allele and late-onset AD. However, {37:Monastero et al. (2005)} and {38:Nacmias et al. (2006)} found no association between polymorphisms in the CST3 gene and AD. A nonsynonymous 73G/A polymorphism in exon 1 of CST3 results in a penultimate A25T missense change ({604312.0002}) in the signal peptide ({42:Radde et al., 2006}). The CST3 thr25 allele has been associated with an increased risk of Alzheimer disease ({16:Finckh et al., 2000}; {11:Cathcart et al., 2005}; {9:Bertram et al., 2007}). It has been suggested that the thr25 variant impairs intracellular cystatin C processing, resulting in impaired secretion and reduced levels of extracellular cystatin C in the plasma of thr25 allele carriers. {30:Kaeser et al. (2007)} showed that overexpression of human cystatin C in brains of amyloid-beta precursor protein (APP; {104760}) transgenic mice reduces cerebral amyloid-beta deposition and that cystatin C binds amyloid-beta and inhibits fibril formation. The results suggested that cystatin C concentrations modulate cerebral amyloidosis risk and provided an opportunity for genetic risk assessment and therapeutic interventions. {36:Mi et al. (2007)} crossed transgenic mice overexpressing human CST3 with mice overexpressing human APP. They showed that cystatin C binds soluble amyloid-beta peptide and inhibits its cerebral amyloid deposition. {36:Mi et al. (2007)} hypothesized that endogenous cystatin C is a carrier of soluble amyloid-beta in cerebral spinal fluid, blood, and brain, where it inhibits amyloid-beta aggregation into insoluble plaques. Age-Related Macular Degeneration 11 In a case-control study, {46:Zurdel et al. (2002)} investigated whether haplotypes A or B (A25T; {604312.0002}) of CST3 were genetically associated with exudative age-related macular degeneration ({611953}) in a Caucasian population. They found that A25T (variant B) may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. textSectionName molecularGenetics geneMapExists true editHistory terry : 04/04/2013 terry : 4/3/2009 terry : 7/3/2008 carol : 4/15/2008 wwang : 1/22/2008 ckniffin : 1/7/2008 alopez : 1/3/2008 alopez : 1/3/2008 terry : 12/20/2007 carol : 8/16/2006 wwang : 4/19/2006 ckniffin : 4/12/2006 terry : 12/20/2005 carol : 12/5/2005 ckniffin : 12/1/2005 tkritzer : 1/3/2005 terry : 12/29/2004 mgross : 5/21/2004 terry : 11/30/1999 terry : 11/24/1999 carol : 11/24/1999 dateCreated Tue, 23 Nov 1999 03:00:00 EST creationDate Victor A. McKusick : 11/23/1999 epochUpdated 1365058800 dateUpdated Thu, 04 Apr 2013 03:00:00 EDT referenceList reference source Scand. J. Clin. Lab. Invest. 48 (suppl. 191): 21-31, 1988. mimNumber 604312 authors Abrahamson, M. title Human cysteine proteinase inhibitors: isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. referenceNumber 1 articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8108423 publisherName HighWire Press title Increased body temperature accelerates aggregation of the leu68-to-gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. mimNumber 604312 referenceNumber 2 publisherAbbreviation HighWire pubmedID 8108423 source Proc. Nat. Acad. Sci. 91: 1416-1420, 1994. authors Abrahamson, M., Grubb, A. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0014-5793(87)80695-6 publisherName Elsevier Science title Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C. mimNumber 604312 referenceNumber 3 publisherAbbreviation ES pubmedID 3495457 source FEBS Lett. 216: 229-233, 1987. authors Abrahamson, M., Grubb, A., Olafsson, I., Lundwall, A. pubmedImages false publisherUrl http://www.elsevier.com/ title The human cystatin C gene (CST3), mutated in hereditary cystatin C amyloid angiopathy, is located on chromosome 20. mimNumber 604312 referenceNumber 4 pubmedID 2567273 source Hum. Genet. 82: 223-226, 1989. authors Abrahamson, M., Islam, M. Q., Szpirer, J., Szpirer, C., Levan, G. pubmedImages false title Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. mimNumber 604312 referenceNumber 5 pubmedID 1352269 source Hum. Genet. 89: 377-380, 1992. authors Abrahamson, M., Jonsdottir, S., Olafsson, I., Jensson, O., Grubb, A. pubmedImages false title Structure and expression of the human cystatin C gene. mimNumber 604312 referenceNumber 6 pubmedID 2363674 source Biochem. J. 268: 287-294, 1990. authors Abrahamson, M., Olafsson, I., Palsdottir, A., Ulvsback, M., Lundwall, A., Jensson, O., Grubb, A. pubmedImages false title SstII polymorphic sites in the promoter region of the human cystatin C gene. mimNumber 604312 referenceNumber 7 pubmedID 1682236 source Hum. Genet. 87: 751-752, 1991. authors Balbin, M., Abrahamson, M. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(84)91302-0 publisherName Elsevier Science title The place of human gamma-trace (cystatin C) amongst the cysteine proteinase inhibitors. mimNumber 604312 referenceNumber 8 publisherAbbreviation ES pubmedID 6203523 source Biochem. Biophys. Res. Commun. 120: 631-636, 1984. authors Barrett, A. J., Davies, M. E., Grubb, A. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1038/ng1934 publisherName Nature Publishing Group title Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. mimNumber 604312 referenceNumber 9 publisherAbbreviation NPG pubmedID 17192785 source Nature Genet. 39: 17-23, 2007. authors Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., Tanzi, R. E. pubmedImages false publisherUrl http://www.nature.com title ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. mimNumber 604312 referenceNumber 10 pubmedID 9008509 source Neurology 48: 139-147, 1997. authors Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C. P., Harrell, L. E., Perry, R. T., Bassett, S. S., Chase, G., Meyers, D., Albert, M. S., Tanzi, R. pubmedImages false articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15728313 publisherName HighWire Press title Cystatin C as a risk factor for Alzheimer disease. mimNumber 604312 referenceNumber 11 publisherAbbreviation HighWire pubmedID 15728313 source Neurology 64: 755-757, 2005. authors Cathcart, H. M., Huang, R., Lanham, I. S., Corder, E. H., Poduslo, S. E. pubmedImages false publisherUrl http://highwire.stanford.edu title Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. mimNumber 604312 referenceNumber 12 pubmedID 6886625 source J. Exp. Med. 158: 623-628, 1983. authors Cohen, D. H., Feiner, H., Jensson, O., Frangione, B. pubmedImages false articleUrl http://www.neurology.org/cgi/pmidlookup?view=long&pmid=10993992 publisherName HighWire Press title A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease. mimNumber 604312 referenceNumber 13 publisherAbbreviation HighWire pubmedID 10993992 source Neurology 55: 763-768, 2000. authors Crawford, F. C., Freeman, M. J., Schinka, J. A., Abdullah, L. I., Gold, M., Hartman, R., Krivian, K., Morris, M. D., Richards, D., Duara, R., Anand, R., Mullan, M. J. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.20968 publisherName John Wiley & Sons, Inc. title Cleavage of cystatin C is not associated with multiple sclerosis. mimNumber 604312 referenceNumber 14 publisherAbbreviation Wiley pubmedID 17006926 source Ann. Neurol. 62: 201-204, 2007. authors Del Boccio, P., Pieragostino, D., Lugaresi, A., Di Ioia, M., Pavone, B., Travaglini, D., D'Aguanno, S., Bernardini, S., Sacchetta, P., Federici, G., Di Ilio, C., Gambi, D., Urbani, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(84)71595-3 publisherName Elsevier Science title Direct mapping of seven genes encoding human type 2 cystatins to a single site located at 20p11.2. mimNumber 604312 referenceNumber 15 publisherAbbreviation ES pubmedID 7896273 source Genomics 24: 172-175, 1994. authors Dickinson, D. P., Zhao, Y., Thiesse, M., Siciliano, M. J. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=11074789 publisherName HighWire Press title Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease. mimNumber 604312 referenceNumber 16 publisherAbbreviation HighWire pubmedID 11074789 source Arch. Neurol. 57: 1579-1583, 2000. authors Finckh, U., von der Kammer, H., Velden, J., Michel, T., Andresen, B., Deng, A., Zhang, J., Muller-Thomsen, T., Zuchowski, K., Menzer, G., Mann, U., Papassotiropoulos, A., {and 14 others} pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=3517880 publisherName HighWire Press title Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). mimNumber 604312 referenceNumber 17 publisherAbbreviation HighWire pubmedID 3517880 source Proc. Nat. Acad. Sci. 83: 2974-2978, 1986. authors Ghiso, J., Jensson, O., Frangione, B. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://linkinghub.elsevier.com/retrieve/pii/0006-291X(86)90475-4 publisherName Elsevier Science title Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. mimNumber 604312 referenceNumber 18 publisherAbbreviation ES pubmedID 3707586 source Biochem. Biophys. Res. Commun. 136: 548-554, 1986. authors Ghiso, J., Pons-Estel, B., Frangione, B. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1007/s10048-004-0174-3 publisherName Springer title Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease. mimNumber 604312 referenceNumber 19 publisherAbbreviation Springer pubmedID 15034766 source Neurogenetics 5: 121-128, 2004. authors Goddard, K. A. B., Olson, J. M., Payami, H., van der Voet, M., Kuivaniemi, H., Tromp, G. pubmedImages false publisherUrl http://www.springeronline.com/ source Cytogenet. Cell Genet. 58: 2029 only, 1991. mimNumber 604312 authors Gopal Rao, V. V., Schnittger, S., Abrahamson, M., Hansmann, I. title Cystatin-C (CST3), the candidate gene for the hereditary cystatin-C amyloid angiopathy (HCCAA) maps to or close to human chromosome 20p11.22. (Abstract) referenceNumber 20 articleUrl http://www.nejm.org/doi/abs/10.1056/NEJM198412133112406?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed publisherName Atypon title Abnormal metabolism of gamma-trace alkaline microprotein: the basic defect in hereditary cerebral hemorrhage with amyloidosis. mimNumber 604312 referenceNumber 21 publisherAbbreviation ATYPON pubmedID 6390199 source New Eng. J. Med. 311: 1547-1549, 1984. authors Grubb, A., Jensson, O., Gudmundsson, G., Arnason, A., Lofberg, H., Malm, J. pubmedImages false publisherUrl http://www.atypon.com/ articleUrl http://www.pnas.org/cgi/pmidlookup?view=long&pmid=6283552 publisherName HighWire Press title Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis. mimNumber 604312 referenceNumber 22 publisherAbbreviation HighWire pubmedID 6283552 source Proc. Nat. Acad. Sci. 79: 3024-3027, 1982. authors Grubb, A., Lofberg, H. pubmedImages false publisherUrl http://highwire.stanford.edu articleUrl http://dx.doi.org/10.1002/ana.20945 publisherName John Wiley & Sons, Inc. title Cystatin C in cerebrospinal fluid and multiple sclerosis. mimNumber 604312 referenceNumber 23 publisherAbbreviation Wiley pubmedID 16900522 source Ann. Neurol. 62: 193-196, 2007. authors Hansson, S. F., Simonsen, A. H., Zetterberg, H., Andersen, O., Haghighi, S., Fagerberg, I., Andreasson, U., Westman-Brinkmalm, A., Wallin, A., Ruetschi, U., Blennow, K. pubmedImages false publisherUrl http://www.interscience.wiley.com/ title Abnormal metabolism or reduced transport of CSF gamma-trace microprotein in hereditary cerebral hemorrhage with amyloidosis. (Letter) mimNumber 604312 referenceNumber 24 pubmedID 3982473 source New Eng. J. Med. 312: 1127-1128, 1985. authors Hochwald, G. M., Thorbecke, G. J. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/037811199400728B publisherName Elsevier Science title Structural organization, expression and chromosomal mapping of the mouse cystatin-C-encoding gene (Cst3). mimNumber 604312 referenceNumber 25 publisherAbbreviation ES pubmedID 7835704 source Gene 152: 221-226, 1995. authors Huh, C., Nagle, J. W., Kozak, C. A., Abrahamson, M., Karlsson, S. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ana.20786 publisherName John Wiley & Sons, Inc. title Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis. mimNumber 604312 referenceNumber 26 publisherAbbreviation Wiley pubmedID 16437581 source Ann. Neurol. 59: 237-247, 2006. authors Irani, D. N., Anderson, C., Gundry, R., Cotter, R., Moore, S., Kerr, D. A., McArthur, J. C., Sacktor, N., Pardo, C. A., Jones, M., Calabresi, P. A., Nath, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ source New York: Walter de Gruyter and Co. (pub.) 1986. mimNumber 604312 authors Jensson, O., Arnason, A., Thorsteinsson, L., Petursdottir, I., Gudmundsson, G., Blondal, H., Grubb, A., Lofberg, H., Luyendijk, W., Bots, G. T. A. M., Frangione, B. title Cystatin C (gamma-trace) amyloidosis.In: Turk, V. : Cysteine Proteinases and their Inhibitors. referenceNumber 27 title Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage. mimNumber 604312 referenceNumber 28 pubmedID 3673496 source Acta Neurol. Scand. 76: 102-114, 1987. authors Jensson, O., Gudmundsson, G., Arnason, A., Blondal, H., Petursdottir, I., Thorsteinsson, L., Grubb, A., Lofberg, H., Cohen, D., Frangione, B. pubmedImages false title The saga of cystatin C gene mutation causing amyloid angiopathy and brain hemorrhage--clinical genetics in Iceland. mimNumber 604312 referenceNumber 29 pubmedID 2689007 source Clin. Genet. 36: 368-377, 1989. authors Jensson, O., Palsdottir, A., Thorsteinsson, L., Arnason, A. pubmedImages false articleUrl http://dx.doi.org/10.1038/ng.2007.23 publisherName Nature Publishing Group title Cystatin C modulates cerebral beta-amyloidosis. mimNumber 604312 referenceNumber 30 publisherAbbreviation NPG pubmedID 18026102 source Nature Genet. 39: 1437-1439, 2007. authors Kaeser, S. A., Herzig, M. C., Coomaraswamy, J., Kilger, E., Selenica, M.-L., Winkler, D. T., Staufenbiel, M., Levy, E., Grubb, A., Jucker, M. pubmedImages false publisherUrl http://www.nature.com articleUrl http://www.eje-online.org/cgi/pmidlookup?view=long&pmid=6353830 publisherName HighWire Press title Occurrence of gamma-trace in the calcitonin-producing C-cells of simian thyroid gland. mimNumber 604312 referenceNumber 31 publisherAbbreviation HighWire pubmedID 6353830 source Acta Endocr. 104: 69-76, 1983. authors Lofberg, H., Grubb, A., Davidsson, L., Kjellander, B., Stromblad, L.-G., Tibblin, S., Olsson, S.-O. pubmedImages false publisherUrl http://highwire.stanford.edu title Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system. mimNumber 604312 referenceNumber 32 pubmedID 119302 source Scand. J. Clin. Lab. Invest. 39: 619-626, 1979. authors Lofberg, H., Grubb, A. O. pubmedImages false articleUrl http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=2436360 publisherName HighWire Press title Immunohistochemical characterization of the amyloid deposits and quantitation of pertinent cerebrospinal fluid proteins in hereditary cerebral hemorrhage with amyloidosis. mimNumber 604312 referenceNumber 33 publisherAbbreviation HighWire pubmedID 2436360 source Stroke 18: 431-440, 1987. authors Lofberg, H., Grubb, A. O., Nilsson, E. K., Jensson, O., Gudmundsson, G., Blondal, H., Arnason, A., Thorsteinsson, L. pubmedImages false publisherUrl http://highwire.stanford.edu source Biomed. Res. 2: 527-535, 1981. mimNumber 604312 authors Lofberg, H., Stromblad, L.-G., Grubb, A. O., Olsson, S.-O. title Demonstration of gamma-trace in normal and neoplastic endocrine A-cells of the pancreatic islets: an immunohistochemical study in monkey, rat and man. referenceNumber 34 articleUrl http://dx.doi.org/10.1002/(SICI)1097-4652(199712)173:3<423::AID-JCP15>3.0.CO;2-C publisherName John Wiley & Sons, Inc. title Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells. mimNumber 604312 referenceNumber 35 publisherAbbreviation Wiley pubmedID 9369956 source J. Cell. Physiol. 173: 423-432, 1997. authors Merz, G. S., Benedikz, E., Schwenk, V., Johansen, T. E., Vogel, L. K., Rushbrook, J. I., Wisniewski, H. M. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/ng.2007.29 publisherName Nature Publishing Group title Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouses models. mimNumber 604312 referenceNumber 36 publisherAbbreviation NPG pubmedID 18026100 source Nature Genet. 39: 1440-1442, 2007. authors Mi, W., Pawlik, M., Sastre, M., Jung, S. S., Radvinsky, D. S., Klein, A. M., Sommer, J., Schmidt, S. D., Nixon, R. A., Mathews, P. M., Levy, E. pubmedImages false publisherUrl http://www.nature.com articleUrl http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=7&issue=4&spage=291 publisherName MetaPress.com title No association between the cystatin C gene polymorphism and Alzheimer's disease: a case-control study in an Italian population. mimNumber 604312 referenceNumber 37 publisherAbbreviation MetaPress pubmedID 16131730 source J. Alzheimers Dis. 7: 291-295, 2005. authors Monastero, R., Camarda, C., Cefalu, A. B., Caldarella, R., Camarda, L. K., Noto, D., Averna, M. R., Camarda, R. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0304-3940(05)01052-9 publisherName Elsevier Science title Cystatin C and apoe polymorphisms in Italian Alzheimer's disease. mimNumber 604312 referenceNumber 38 publisherAbbreviation ES pubmedID 16188386 source Neurosci. Lett. 392: 110-113, 2006. authors Nacmias, B., Bagnoli, S., Tedde, A., Cellini, E., Guarnieri, B. M., Bartoli, A., Serio, A., Piacentini, S., Sorbi, S. pubmedImages false publisherUrl http://www.elsevier.com/ title The human cystatin C gene promoter: functional analysis and identification of heterogeneous mRNA. mimNumber 604312 referenceNumber 39 pubmedID 8633184 source Scand. J. Clin. Lab. Invest. 55: 597-607, 1995. authors Olafsson, I. pubmedImages false articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(88)90641-1 publisherName Elsevier Science title Mutation in cystatin C gene causes hereditary brain haemorrhage. mimNumber 604312 referenceNumber 40 publisherAbbreviation ES pubmedID 2900981 source Lancet 322: 603-604, 1988. Note: Originally Volume II. authors Palsdottir, A., Abrahamson, M., Thorsteinsson, L., Arnason, A., Olafsson, I., Grubb, A., Jensson, O. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1002/ana.20545 publisherName John Wiley & Sons, Inc. title Cystatin C expression is associated with granule cell dispersion in epilepsy. mimNumber 604312 referenceNumber 41 publisherAbbreviation Wiley pubmedID 16049933 source Ann. Neurol. 58: 211-223, 2005. authors Pirttila, T. J., Manninen, A., Jutila, L., Nissinen, J., Kalviainen, R., Vapalahti, M., Immonen, A., Paljarvi, L., Karkola, K., Alafuzoff, I., Mervaala, E., Pitkanen, A. pubmedImages false publisherUrl http://www.interscience.wiley.com/ articleUrl http://dx.doi.org/10.1038/sj.embor.7400784 publisherName Nature Publishing Group title A-beta-42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. mimNumber 604312 referenceNumber 42 publisherAbbreviation NPG pubmedID 16906128 source EMBO Reports 7: 940-946, 2006. authors Radde, R., Bolmont, T., Kaeser, S. A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M. E., Jaggi, F., Wolburg, H., Gengler, S., Haass, C., Bhetti, B., Czech, C., Holscher, C., Mathews, P. M., Jucker, M. pubmedImages true publisherUrl http://www.nature.com articleUrl http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71139-0 publisherName Elsevier Science title Cystatin C (CST3), the candidate gene for hereditary cystatin C amyloid angiopathy (HCCAA), and other members of the cystatin gene family are clustered on chromosome 20p11.2. mimNumber 604312 referenceNumber 43 publisherAbbreviation ES pubmedID 8486384 source Genomics 16: 50-55, 1993. Note: Erratum: Genomics 17: 533 only, 1993. authors Schnittger, S., Gopal Rao, V. V. N., Abrahamson, M., Hansmann, I. pubmedImages false publisherUrl http://www.elsevier.com/ articleUrl http://dx.doi.org/10.1172/JCI7709 publisherName Journal of Clinical Investigation title Cystatin C deficiency in human atherosclerosis and aortic aneurysms. mimNumber 604312 referenceNumber 44 publisherAbbreviation JCI pubmedID 10545518 source J. Clin. Invest. 104: 1191-1197, 1999. authors Shi, G.-P., Sukhova, G. K., Grubb, A., Ducharme, A., Rhode, L. H., Lee, R. T., Ridker, P. M., Libby, P., Chapman, H. A. pubmedImages true publisherUrl http://www.jci.org source Ann. Neurol. 62: 205 only, 2007. mimNumber 604312 authors Wheeler, D., Jelinek, C., Anderson, C., Gundry, R., Irani, D., Calbresi, P., Cotter, R., Nath, A. title Reply. referenceNumber 45 articleUrl http://bjo.bmj.com/cgi/pmidlookup?view=long&pmid=11815350 publisherName HighWire Press title CST3 genotype associated with exudative age-related macular degeneration. mimNumber 604312 referenceNumber